Neuroactive enantiomeric 15-, 16- and 17-substituted steroids as modulators for GABA type-A receptors

ABSTRACT

The present disclosure is generally directed to neuroactive enantiomeric 15-, 16- and 17-substituted steroids with additional optional substituents at carbons 3, 4, 6, 7, 10 and 13, and pharmaceutically acceptable salts thereof, for use as, for example, modulators for GABA type-A receptors. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Patent Application ofInternational Application Serial Number PCT/US2014/016405, filed Feb.14, 2014, which is incorporated herein in its entirety, and which claimspriority benefit of U.S. Provisional Patent Application Ser. No.61/765,228, filed on Feb. 15, 2013, the entire contents of which arealso incorporated herein by reference.

GOVERNMENT SUPPORT

The claimed subject matter was developed with Government support underNIH Grant #GM47969, awarded by the National Institute of Health.Accordingly, the Government has certain rights in the claimed subjectmatter.

BACKGROUND OF THE DISCLOSURE

The present disclosure is generally directed to novel compounds havingutility as an anesthetic and/or in the treatment of disorders relatingto GABA function and activity. More specifically, the present disclosureis directed to neuroactive enantiomeric 15-, 16- and 17-substitutedsteroids, and more specifically ent-steroids, with additional optionalsubstituents at carbons 3, 4, 6, 7, 10 and 13, and pharmaceuticallyacceptable salts thereof for use as, for example, an anesthetic, as wellas pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions containing them. The present disclosure is generallydirected to, for use as, for example, modulators for GABA type-Areceptors. The present disclosure is further directed to pharmaceuticalcompositions comprising such compounds.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitterof the central nervous system. GABA activates two types of receptors,the inotropic GABA_(A) and the metabotropic GABA_(B) receptor.Activation of the GABA_(B) receptor by GABA causes hyperpolarization anda resultant inhibition of neurotransmitter release. The GABA_(A)receptor subtype regulates neuronal excitability and rapid mood changes,such as anxiety, panic, and stress response. GABA_(A) receptors arechloride ion channels; as a result, activation of the receptor inducesincreased inward chloride ion flux, resulting in membranehyperpolarization and neuronal inhibition. Drugs that stimulate GABA_(A)receptors, such as benzodiazepines and barbiturates, have anticonvulsiveeffects (by reducing neuronal excitability and raising the seizurethreshold), as well as anxiolytic and anesthetic effects.

The effect of certain steroids on GABA_(A) receptors has beenwell-established. As a result, researchers continue to pursue thediscovery and synthesis of neuroactive steroids that may act asanesthetics and/or that may serve to provide treatment for disordersrelated to GABA function. In addition to anesthetic properties,neuroactive steroids may be used to treat disorders related to GABAfunction. For example, neuroactive steroids, such as progesterone, maybe used as sedative-hypnotics, exhibiting benzodiazepine-like actions,inducing reduced sleep latency and increased non-REM sleep with onlysmall changes in slow wave and REM sleep. Further, drugs that enhanceGABA responses are often used to treat anxiety in humans. Thus, it mightbe expected that GABA-potentiating steroids would exhibit anxiolyticeffects. Neuroactive steroids may also be used to treat depression,given that accumulating evidence suggests that patients with majordepression have decreased levels of GABAergic neurosteroids and thatcertain treatments for depression alter levels of these steroids.Although GABA is not typically thought to play a critical role in thebiology of depression, there is evidence that low GABAergic activity maypredispose one to mood disorders. Finally, inhibition of NMDA receptorsand enhancement of GABA_(A) receptors appear to play important roles inmediating the acute effects of ethanol in the nervous system, whilerelated studies suggest that GABAergic neurosteroids may be involved insome of the pharmacological effects of ethanol and that neuroactivesteroids may be useful in treating ethanol withdrawal.

For example, the steroids nat-allopregnanolone (nat-1) and pregnanolone(nat-2) are known to function as allosteric modulators of GABA_(A)receptor that enhance the actions of the neurotransmitter GABA.

The allosteric modulation of this receptor by the mirror images(enantiomers) of these compounds, ent-allopregnanolone (ent-1) andent-pregnanolone (ent-2) are known to be weaker.

Similarly, the steroids androsterone (nat-3) and etiocholanolone (nat-4)are also allosteric modulators of GABA_(A) receptors.

Surprisingly, the enantiomers of these two compounds, ent-androsterone(ent-3) and ent-etiocholanolone (ent-4), have greater activity thansteroids nat-3 and nat-4. Androsterone and ent-androsterone are alignedat a common binding site on GABA_(A) receptors.

Because ent-3 and ent-4 are effective allosteric enhancers of GABAaction at GABA_(A) receptors, there is a need to research whetheradditional compounds having the absolute configuration of ent-3 andent-4 could be effective allosteric modulators of GABA_(A) receptorfunction.

In view of the foregoing, it is clear that there are a number ofpotentially advantageous uses for neurosteroids. As a result, there is acontinuing need for the further synthesis and understanding of newneuroactive steroids, particularly those having utility as an anestheticand/or in the treatment of a disorder relating to GABA function andactivity.

The present disclosure has found previously unknown ent-steroids havingthis activity that are effective enhancers of GABA_(A) receptorfunction.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure is directed to a compound having astructure of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

R₁ is H or —C(O)—R_(z), where R_(z) is optionally substituted C₁-C₂₀alkyl;

R₂ is H, optionally substituted C₁-C₄ alkoxy, aryloxy, morpholinyl,optionally substituted C₂-C₄, alkenoxy, optionally substituted C₂-C₄alkynoxy, or —O—C(O)—R_(x), where R_(x) is optionally substituted C₁-C₂₀alkyl;

R₃ is H, OH, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, aryloxy, acetyl,substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R_(u), whereR_(u) is optionally substituted C₁-C₂₀ alkyl;

R₄ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(t),where R_(t) is optionally substituted C₁-C₂₀ alkyl;

with the proviso that when R₃ and R₄ are taken together, R₃ and R₄combine to form ═O or ═CR_(y), (where R_(y) is CN, CH₂NH₂, C(O)—O—R_(w)(where R_(w) is H, optionally substituted C₁-C₁₀ or optionallysubstituted phenyl), or CH₂OR_(v) (where R_(v) is H, optionallysubstituted C₁-C₁₀, optionally substituted phenyl, or optionallysubstituted napthyl));

R₅ is H, OH, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, aryloxy, acetyl,substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R_(s), whereR_(s) is optionally substituted C₁-C₂₀ alkyl;

R₆ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(r),where R_(r) is optionally substituted C₁-C₂₀ alkyl;

with the proviso that when R₅ and R₆ are taken together, R₅ and R₆combine to form ═O or ═CR_(q), (where R_(q) is CN, CH₂NH₂, C(O)—O—R_(p)(where R_(p) is H, optionally substituted C₁-C₁₀ or optionallysubstituted phenyl), or CH₂OR_(o) (where R_(o) is H, optionallysubstituted C₁-C₁₀, optionally substituted phenyl, or optionallysubstituted napthyl));

R₇ is H, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, spirooxirane,cyano, ═O, nitro or optionally substituted COCH₃;

R₈ is H, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, spirooxirane,cyano, ═O, ═CHCN, nitro or optionally substituted COCH₃;

R₉ is H, optionally substituted C₁-C₄ alkoxy, spiroepoxide or ═O;

R₁₀ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₁₁ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₁₂ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; and,

- - - denotes an optional, additional C—C bond, resulting in a C═C bondbetween C₄-C₅, C₅-C₆, C₆-C₇, C₇-C₈, C₁₅-C₁₆, and/or C₁₆-C₁₇;

with the provisos that:

when R₅ is benzyloxy in the alpha configuration and R₆ is H, R₉ is otherthan ═O or spiroepoxide;

when R₁-R₈ and R₁₂ are H, R₁₀ and R₁₁ are CH₃, R₉ is other than ═O orspiroepoxide;

when R₁-R₈ and R₁₁-R₁₂ are H, R₁₀ is CH₃, and the C₅—H is in the alphaposition, R₉ is other than ═O; or,

when a double bond is present between C₅-C₆, R₁ is other than H or R₉ isother than ═O.

The present disclosure is still further directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of one or moreof the above-noted enantiomeric steroids or pharmaceutically acceptablesalts thereof, and optionally a pharmaceutically acceptable carrier. Thepresent disclosure also provides kits comprising ent-steroids, saltsthereof, and/or pharmaceutical compositions thereof.

The present disclosure further provides methods of inducing anesthesiain a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of one or more of theabove-noted enantiomeric steroids, or pharmaceutically acceptable saltsthereof, or a pharmaceutical composition thereof.

The present disclosure further provides methods of treating disordersrelated to GABA function in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of one or more of the above-noted enantiomeric steroids, orpharmaceutically acceptable salts thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the disorder is selectedfrom the group consisting of insomnia, mood disorders, convulsivedisorders, Fragile X syndrome, anxiety, or symptoms of ethanolwithdrawal.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 discloses graphical data of the duration of anesthesia induced bytail vein injections of compounds of the present disclosure relative toan anesthetic steroid.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

In accordance with the present disclosure, it has been discovered thatcompounds having an enantiomeric 15-, 16- and 17-substituted steroid,more specifically an ent-steroid, with additional optional substituentsat carbons 3, 4, 6, 7, 10 and 13 structure are neuroactive and are alsosuitable for use as anesthetics and in the treatment of disordersassociated with GABA function, as well as pharmaceutically acceptablesalts thereof. The compounds may be used, for example, as an effectivecontinuous infusion sedative for non-surgical procedures (e.g.,colonoscopy). The compounds also offer advantages over anesthetics knownin the art, such as a lower likelihood for bacterial contamination, aswell as an improved relationship with solubilizing agents.

1. Steroid Structure

Generally speaking, the enantiomeric steroids (ent-steroids) of thepresent disclosure have the opposite absolute configuration of anynaturally occurring steroids. The ent-steroid of the present disclosurehas a tetracyclic, fused ring structure, such as acyclopenta[a]phenanthrene ring system (an embodiment of which isillustrated and discussed in greater detail below), wherein the C₃, C₄,C₆, C₇, C₁₀ and C₁₃ positions have optional substituents in conjunctionwith an optional substituent at the C₁₅, C₁₆ and C₁₇ positions.

More particularly, however, the present disclosure is directed, incertain embodiments, to an ent-steroid having the structure of Formula(I):

or a pharmaceutically acceptable salt thereof; wherein:

R₁ is H or —C(O)—R_(z), where R_(z) is optionally substituted C₁-C₂₀alkyl;

R₂ is H, optionally substituted C₁-C₄ alkoxy, aryloxy, morpholinyl,optionally substituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄alkynoxy, or —O—C(O)—R_(x), where R_(x) is optionally substituted C₁-C₂₀alkyl;

R₃ is H, OH, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, aryloxy, acetyl,substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R_(u), whereR_(u) is optionally substituted C₁-C₂₀ alkyl;

R₄ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(t),where R_(t) is optionally substituted C₁-C₂₀ alkyl;

with the proviso that when R₃═R₄, R₃ and R₄ are ═O or ═CR_(y), (whereR_(y) is CN, CH₂NH₂, C(O)—O—R_(w) (where R_(w) is H, optionallysubstituted C₁-C₁₀ or optionally substituted phenyl), or CH₂OR_(v)(where R_(v) is H, optionally substituted C₁-C₁₀, optionally substitutedphenyl, or optionally substituted napthyl));

R₅ is H, OH, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, aryloxy, acetyl,substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R_(s), whereR_(s) is optionally substituted C₁-C₂₀ alkyl;

R₆ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(r),where R_(r) is optionally substituted C₁-C₂₀ alkyl;

with the proviso that when R₅═R₆, R₅ and R₆ are ═O or ═CR_(q), (whereR_(q) is CN, CH₂NH₂, C(O)—O—R_(p) (where R_(p) is H, optionallysubstituted C₁-C₁₀ or optionally substituted phenyl), or CH₂OR_(o)(where R_(o) is H, optionally substituted C₁-C₁₀, optionally substitutedphenyl, or optionally substituted napthyl));

R₇ is H, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, spirooxirane,cyano, ═O, nitro or optionally substituted COCH₃;

R₈ is H, optionally substituted C₁-C₄ alkoxy, optionally substitutedC₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, spirooxirane,cyano, ═O, ═CHCN, nitro or optionally substituted COCH₃;

R₉ is H, optionally substituted C₁-C₄ alkoxy, spiroepoxide or ═O;

R₁₀ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₁₁ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl;

R₁₂ is H, optionally substituted C₁-C₄ alkyl, optionally substitutedC₂-C₄ alkenyl, or optionally substituted C₂-C₄ alkynyl; and,

- - - denotes an optional, additional C—C bond, resulting in a C═C bondbetween C₄-C₅, C₅-C₆, C₆-C₇, C₇-C₈, C₁₅-C₁₆, and/or C₁₆-C₁₇;

with the provisos that:

when R₅ is benzyloxy in the alpha configuration and R₆ is H, R₉ is otherthan ═O or spiroepoxide;

when R₁-R₈ and R₁₂ are H, R₁₀ and R₁₁ are CH₃, R₉ is other than ═O orspiroepoxide;

when R₁-R₈ and R₁₁-R₁₂ are H, R₁₀ is CH₃, and the C₅—H is in the alphaposition, R₉ is other than ═O; or,

when a double bond is present between C₅-C₆, R₁ is other than H or R₉ isother than ═O.

As generally defined above, R₁ is H or —C(O)—R_(z), where R_(z) isoptionally substituted C₁-C₂₀ alkyl. In one embodiment, R_(z) isoptionally substituted C₁-C₁₅ alkyl, preferably optionally substitutedC₁-C₁₀ alkyl, more preferably optionally substituted C₁-C₄ alkyl. In apreferred embodiment, R₁ is H. In another preferred embodiment, when R₁is H, the OH at C₃ is in the beta configuration.

As generally defined above, R₂ is H, optionally substituted C₁-C₄alkoxy, optionally substituted C₂-C₄ alkenoxy, optionally substitutedC₂-C₄ alkynoxy, aryloxy, morpholinyl or —O—C(O)—R_(x), where R_(x) isoptionally substituted C₁-C₂₀ alkyl. In one embodiment, R_(x) isoptionally substituted C₁-C₁₅ alkyl, preferably optionally substitutedC₁-C₁₀ alkyl, more preferably optionally substituted C₁-C₄ alkyl. In oneembodiment, R₂ is selected from the group consisting of H and methoxy(i.e., —OCH₃). In certain embodiments, R₂ is H. In other certainembodiments, R₂ is methoxy. In certain embodiments, R₂, when not H andno double bond is present between C₄-C₅, is in the alpha configuration.In certain embodiments, when R₂ is methoxy, R₂ is in the alphaconfiguration.

As generally defined above, R₃ is H, OH, optionally substituted C₁-C₄alkoxy, optionally substituted C₂-C₄ alkenoxy, optionally substitutedC₂-C₄ alkynoxy, aryloxy, acetyl, substituted acetyl, cyano, nitro,spiroepoxide or —O—C(O)—R_(u), where R_(u) is optionally substitutedC₁-C₂₀ alkyl. In one embodiment, R_(u) is optionally substituted C₁-C₁₅alkyl, preferably optionally substituted C₁-C₁₀ alkyl, more preferablyoptionally substituted C₁-C₄ alkyl. In a preferred embodiment, R₃ is H,or, alternatively, R₃ is taken together with R₄ to be ═O.

As generally defined above, R₄ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl or —O—C(O)—R_(t), where R_(t) is optionally substituted C₁-C₂₀alkyl. In one embodiment, R_(t) is optionally substituted C₁-C₁₅ alkyl,preferably optionally substituted C₁-C₁₀ alkyl, more preferablyoptionally substituted C₁-C₄ alkyl. In a preferred embodiment, R₄ is H,or, alternatively, as noted above R₄ is taken together with R₃ to be ═O.

As generally defined above, with respect to R₃ and R₄, when takentogether, R₃ and R₄ combine to form ═O or ═CR_(y), (where R_(y) is CN,CH₂NH₂, C(O)—O—R_(w) (where R_(w) is H, optionally substituted C₁-C₁₀ oroptionally substituted phenyl), or CH₂OR_(v) (where R_(v) is H,optionally substituted C₁-C₁₀, optionally substituted phenyl, oroptionally substituted napthyl)).

As generally defined above, R₅ is H, OH, optionally substituted C₁-C₄alkoxy, optionally substituted C₂-C₄ alkenoxy, optionally substitutedC₂-C₄ alkynoxy, aryloxy, acetyl, substituted acetyl, cyano, nitro,spiroepoxide or —O—C(O)—R_(s), where R_(s) is optionally substitutedC₁-C₂₀ alkyl. In one embodiment, R_(s) is optionally substituted C₁-C₁₅alkyl, preferably optionally substituted C₁-C₁₀ alkyl, more preferablyoptionally substituted C₁-C₄ alkyl. In a preferred embodiment, R₅ is H.

As generally defined above, R₆ is H, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl or —O—C(O)—R_(r), where R_(r) is optionally substituted C₁-C₂₀alkyl. In one embodiment, R_(r) is optionally substituted C₁-C₁₅ alkyl,preferably optionally substituted C₁-C₁₀ alkyl, more preferablyoptionally substituted C₁-C₄ alkyl. In a preferred embodiment, R₆ is H.

As generally defined above, with respect to R₅ and R₆, when takentogether, R₅ and R₆ combine to form ═O or ═CR_(q), (where R_(q) is CN,CH₂NH₂, C(O)—O—R_(p) (where R_(p) is H, optionally substituted C₁-C₁₀ oroptionally substituted phenyl), or CH₂OR_(o) (where R_(o) is H,optionally substituted C₁-C₁₀, optionally substituted phenyl, oroptionally substituted napthyl)).

As generally defined above, R₇ is H, optionally substituted C₁-C₄alkoxy, optionally substituted C₂-C₄ alkenoxy, optionally substitutedC₂-C₄ alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substitutedCOCH₃. In a preferred embodiment, R₇ is H, or, alternatively, R₇ is—OCH₃. In certain embodiments, R₇, when not ═O, is in the alphaconfiguration (e.g., when R₇ is —OCH₃).

As generally defined above, R₈ is H, optionally substituted C₁-C₄alkoxy, optionally substituted C₂-C₄ alkenoxy, optionally substitutedC₂-C₄ alkynoxy, spirooxirane, cyano, ═O, ═CHCN, nitro or optionallysubstituted COCH₃. In a preferred embodiment, R₈ is ═O, or,alternatively, R₈ is —OCH₃, COCH₃, CN, or ═CHCN. In certain embodiments,R₈, when not ═O, is in the alpha configuration.

As generally defined above, R₉ is H, optionally substituted C₁-C₄alkoxy, spiroepoxide or ═O. In a preferred embodiment, R₉ is ═O. Incertain embodiments, R₉, when not ═O, is in the alpha configuration.

As generally defined above, R₁₀ is H, optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, or optionally substitutedC₂-C₄ alkynyl. In certain embodiments, R₁₀ is selected from the groupconsisting of H and methyl. In one embodiment, R₁₀ is H. In anotherembodiment, R₁₀ is methyl. R₁₀ is preferably in the alpha configuration.

As generally defined above, R₁₁ is H, optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, or optionally substitutedC₂-C₄ alkynyl. In certain embodiments, R₁₁ is selected from the groupconsisting of H and methyl. In one embodiment, R₁₁ is H. In anotherembodiment, R₁₁ is methyl. R₁₁ is preferably in the alpha configuration.

As generally defined above, R₁₂ is H, optionally substituted C₁-C₄alkyl, optionally substituted C₂-C₄ alkenyl, or optionally substitutedC₂-C₄ alkynyl. In certain embodiments, R₁₂ is selected from the groupconsisting of H and methyl. In one embodiment, R₁₂ is H. In anotherembodiment, R₁₂ is methyl. In a preferred embodiment, when R₁₂ ismethyl, R₁₂ is in the alpha configuration.

As generally defined above, - - - denotes an optional, additional C—Cbond, resulting in either a C═C bond between C₄-C₅, C₅-C₆, C₆-C₇, C₇-C₈,C₁₅-C₁₆, and/or C₁₆-C₁₇ with the proviso that when present at C₄-C₅ orC₅-C₆, the C₅—H substituent is not present; when present at C₅-C₆ orC₆-C₇, one of R₃ and R₄ are not present; when present at C₆-C₇ or C₇-C₈,one of R₅ and R₆ are not present; and, when present at C₇-C₈, the C₈—Hsubstituent is not present. When a C═C bond is present between C₁₅-C₁₆or C₁₆-C₁₇, it is to be understood that a H (not shown) is absent fromthe carbon atoms between which the C═C is present.

In certain embodiments, the additional C—C bond(s) are absent, and thehydrogen at C₅ is in the alpha or beta position. In certain embodiments,the additional C—C bond is absent, and the hydrogen at C₅ is in thealpha (down) position. In certain embodiments, the additional C—C bondis absent, and the hydrogen at C₅ is in the beta (up) position.

In certain embodiments, the additional C—C bond(s) are absent, and thehydrogen at C₈ is in the alpha position. In other certain embodiments,the C₉—H substituent is in the beta configuration. In other certainembodiments, the C₁₄—H is in the beta configuration. In other certainembodiments, C₁₄—H is in the alpha configuration.

As generally defined above, when R₅ is benzyloxy in the alphaconfiguration and R₆ is H, R₉ is other than ═O or spiroepoxide. Further,when R₁-R₈ and R₁₂ are H, R₁₀ and R₁₁ are CH₃, R₉ is other than ═O orspiroepoxide. Additionally, when R₁-R₈ and R₁₁-R₁₂ are H, R₁₀ is CH₃,and the C₅—H is in the alpha position, R₉ is other than ═O.Additionally, when a double bond is present between C₅-C₆, R₁ is otherthan H or R₉ is other than ═O.

It is to be noted that the present disclosure contemplates and isintended to encompass all of the various combinations and permutations(i.e., combinations of substituent options, locations and stereochemicalconfigurations) possible here, with the exception of those structuresnoted above.

Accordingly, as noted, the ent-steroid of Formula (I) may encompass anumber of various structures in accordance with the present disclosure.

Exemplary compounds of Formula (I) include, but are not limited to, thefollowing:

and pharmaceutically acceptable salts thereof.

In this regard it is to be noted that the structures provided above areof various exemplary embodiments. As such, they should not be viewed ina limiting sense.

2. Methods of Preparation and Pharmaceutical Compositions

It is to be noted that the compounds or ent-steroids of the presentdisclosure may in various embodiments be prepared or used in accordancewith means generally known in the art. For example, in certainembodiments, the ent-steroids of the present disclosure may be preparedor used in a pharmaceutically acceptable salt form. Suitable salt formsinclude, for example, citrate or chloride salt forms.

In various embodiments of the present disclosure, a pharmaceuticalcomposition is disclosed that may comprise an ent-steroid in accordancewith the formulas of the present disclosure. The compounds orent-steroids of the present disclosure, as well as the various saltforms and other pharmaceutically acceptable forms, e.g., solvates and/orhydrates of compounds described herein, and pharmaceutical compositionscontaining them, may in general be prepared using methods and techniquesknown in the art, and/or as described in the Examples provided herein.

Without wishing to be bound by any particular theory, the compounds orent-steroids of the present disclosure are useful for potentiating GABAat GABA_(A) receptors thereby inducing anesthesia or treating disordersrelated to GABA function (e.g., insomnia, mood disorders, Fragile Xsyndrome, convulsive disorders, anxiety disorders, or symptoms ofethanol withdrawal) in a subject, e.g., a human subject, and arepreferably administered in the form of a pharmaceutical compositioncomprising an effective amount of a compound of the instant disclosureand optionally a pharmaceutically or pharmacologically acceptablecarrier.

In one aspect, provided is a method of inducing anesthesia in a subjectin need thereof, the method comprising administering to the subject atherapeutically effective amount of one or more of the above-notedent-steroids, or pharmaceutically acceptable salts thereof, or apharmaceutical composition thereof.

In another aspect, provided is a method of treating disorders related toGABA function in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of oneor more of the above-noted ent-steroids, or pharmaceutically acceptablesalts thereof, or a pharmaceutical composition thereof. In certainembodiments, the disorder is selected from the group consisting ofinsomnia, mood disorders, convulsive disorders, Fragile X syndrome,anxiety, or symptoms of ethanol withdrawal.

In one embodiment of the present disclosure, a therapeutically effectiveamount of compound is from about 5 mg/kg to about 20 mg/kg, about 5mg/kg to about 18 mg/kg, about 5 mg/kg to about 16 mg/kg, about 5 mg/kgto about 14 mg/kg, about 5 mg/kg to about 12 mg/kg, about 5 mg/kg toabout 10 mg/kg, about 6 mg/kg to about 10 mg/kg, about 6 mg/kg to about9 mg/kg, about 7 mg/kg to about 9 mg/kg, or about 8 mg/kg to about 16mg/kg. In certain embodiments, a therapeutically effective amount of thecompound is about 8 mg/kg. It will be appreciated that dose ranges asdescribed herein provide guidance for the administration of providedpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, identity of the particularcompound(s), mode of administration, and the like. The desired dosagecan be delivered three times a day, two times a day, once a day, everyother day, every third day, every week, every two weeks, every threeweeks, or every four weeks. In certain embodiments, the desired dosagecan be delivered using multiple administrations (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or more administrations). In other certain embodiments, the compound maybe administered via continuous intravenous (IV) infusion, such as usedby those commonly skilled in the art of general anesthesia.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compounds or compositions can beadministered in combination with additional therapeutically activeagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. It will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the inventive compound with the additional therapeutically activeagent and/or the desired therapeutic effect to be achieved. In general,it is expected that additional therapeutically active agents utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually. Exemplarytherapeutically active agents include small organic molecules such asdrug compounds (e.g., compounds approved by the US Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins and cells.

The pharmaceutical composition may also be in combination with at leastone pharmacologically acceptable carrier. The carrier, also known in theart as an excipient, vehicle, auxiliary, adjuvant, or diluent, is anysubstance that is pharmaceutically inert, confers a suitable consistencyor form to the composition, and does not diminish the therapeuticefficacy of the compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic, or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the compounds or ent-steroidsof the present disclosure may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the disclosure can be formulated for any route ofadministration, so long as the target tissue is available via thatroute. Suitable routes of administration include, but are not limitedto, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous,rectal, subcutaneous, intramuscular, intraorbital, intracapsular,intraspinal, intraperitoneal, or intrasternal), topical (nasal,transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual, andintestinal administration. In certain embodiments, the route ofadministration is oral. In certain embodiments, the route ofadministration is parenteral. In certain embodiments, the route ofadministration is intravenous.

Pharmaceutically acceptable carriers for use in the compositions of thepresent disclosure are well known to those of ordinary skill in the artand are selected based upon a number of factors, including for example:the particular compound used, and its concentration, stability andintended bioavailability; the disease, disorder or condition beingtreated with the composition; the subject, its age, size and generalcondition; and/or the route of administration. Suitable carriers may bereadily determined by one of ordinary skill in the art. (See, forexample, J. G. Nairn, in: Remington's Pharmaceutical Science (A.Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517.)

The compositions may be formulated as tablets, dispersible powders,pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions,suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, orany other dosage form that can be administered orally. Techniques andcompositions for making oral dosage forms useful in the presentdisclosure are described in the following exemplary references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and,Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the present disclosure designed for oraladministration comprise an effective amount of a compound of thedisclosure in a pharmaceutically acceptable carrier. Suitable carriersfor solid dosage forms include sugars, starches, and other conventionalsubstances including lactose, talc, sucrose, gelatin,carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate,calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, cornstarch, potato starch, sodium saccharin, magnesium carbonate,tragacanth, microcrystalline cellulose, colloidal silicon dioxide,croscarmellose sodium, talc, magnesium stearate, and stearic acid.Further, such solid dosage forms may be uncoated or may be coated byknown techniques (e.g., to delay disintegration and absorption).

The ent-steroids of the present disclosure may also be formulated forparenteral administration (e.g., formulated for injection viaintravenous, intraarterial, subcutaneous, rectal, subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes). The compositions of thepresent disclosure for parenteral administration comprise an effectiveamount of the compound in a pharmaceutically acceptable carrier. Dosageforms suitable for parenteral administration include solutions,suspensions, dispersions, emulsions or any other dosage form that can beadministered parenterally. Techniques and compositions for makingparenteral dosage forms are known in the art. Typically formulations forparenteral administration are sterile or are sterilized beforeadministration.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide, 2-pyrrolidinone,1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g.,1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such asmonoacetin, diacetin, and triacetin, aliphatic or aromatic esters suchas ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzylacetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di,or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate,ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters ofsorbitan, fatty acid derived PEG esters, glyceryl monostearate,glyceride esters such as mono, di, or tri-glycerides, fatty acid esterssuch as isopropyl myristrate, fatty acid derived PEG esters such asPEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone,pluronic 60, polyoxyethylene sorbitol oleic polyesters such aspoly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀monooleate, poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono-ricinoleate, polyoxyethylene sorbitan esters(such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and POLYSORBATE® 20, 40, 60 or 80from ICI Americas, Wilmington, Del.), polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters (such as polyoxyl 40 hydrogenated castor oil,cyclodextrins or modified cyclodextrins (e.g.,beta-hydroxypropyl-cyclodextrin)), saccharide fatty acid esters (i.e.,the condensation product of a monosaccharide (e.g., pentoses, such asribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses suchas glucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfone, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzine; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(SOLUTOL® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in the disclosure arewell known to those of ordinary skill in the art, and are identified inThe Handbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa.,1995), The United States Pharmacopeia 24, The National Formulary 19,(National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al.,and Use of Nonaqueous Solvents in Parenteral Products, J. of Pharm.Sciences, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include cyclodextrins or modified cyclodextrins(e.g., beta-hydroxypropyl-cyclodextrin) as well as oils rich intriglycerides, for example, safflower oil, soybean oil or mixturesthereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40hydrogenated castor oil. Commercially available triglycerides includeINTRALIPID® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), NUTRALIPID® emulsion (McGaw, Irvine, Calif.), LIPOSYN® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), LIPOSYN® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(DHASCO® (from Martek Biosciences Corp., Columbia, Md.), DHA MAGURO®(from Daito Enterprises, Los Angeles, Calif.), SOYACAL®, andTRAVEMULSION®.

Additional minor components can be included in the compositions of thedisclosure for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the compound at the site of administration,protect the stability of the composition, control the pH, facilitateprocessing of the compound into pharmaceutical formulations, and thelike. Preferably, each of these components is individually present inless than about 15 wt % of the total composition, more preferably lessthan about 5 wt %, and most preferably less than about 0.5 wt % of thetotal composition. Some components, such as fillers or diluents, canconstitute up to 90 wt % of the total composition, as is well known inthe formulation art. Such additives include cryoprotective agents forpreventing reprecipitation, surface active, wetting or emulsifyingagents (e.g., lecithin, polysorbate-80, TWEEN® 80, Pluronic 60,polyoxyethylene stearate), preservatives (e.g.,ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol,phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben),agents for adjusting pH or buffering agents (e.g., acids, bases, sodiumacetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g.,glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetylalcohol, stearyl alcohol, guar gum, methyl cellulose,hydroxypropylcellulose, tristearin, cetyl wax esters, polyethyleneglycol), colorants, dyes, flow aids, non-volatile silicones (e.g.,cyclomethicone), clays (e.g., bentonites), adhesives, bulking agents,flavorings, sweeteners, adsorbents, fillers (e.g., sugars such aslactose, sucrose, mannitol, or sorbitol, cellulose, or calciumphosphate), diluents (e.g., water, saline, electrolyte solutions),binders (e.g., starches such as maize starch, wheat starch, rice starch,or potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropyl methylcellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents(e.g., starches such as maize starch, wheat starch, rice starch, potatostarch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone,agar, alginic acid or a salt thereof such as sodium alginate,croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc,stearic acid or salts thereof such as magnesium stearate, orpolyethylene glycol), coating agents (e.g., concentrated sugar solutionsincluding gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, or titanium dioxide), and antioxidants (e.g.,sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose,phenols, and thiophenols).

Dosage from administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Those with ordinary skill in administering anesthetics can readilydetermine dosage and regimens for the administration of thepharmaceutical compositions of the disclosure or titrating to aneffective dosage for use in treating insomnia, mood disorders,convulsive disorders, anxiety or symptoms of ethanol withdrawal. It isunderstood that the dosage of the compounds will be dependent upon theage, sex, health, and weight of the recipient, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired. For any mode of administration, the actual amount of compounddelivered, as well as the dosing schedule necessary to achieve theadvantageous effects described herein, will also depend, in part, onsuch factors as the bioavailability of the compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present disclosureshould be sufficient to affect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the compound, whether administered orally or by another route, is anyamount that would result in a desired therapeutic response whenadministered by that route. The dosage may vary depending on the dosingschedule, which can be adjusted as necessary to achieve the desiredtherapeutic effect. The most preferred dosage will be tailored to theindividual subject, as is understood and determinable by one of ordinaryskill in the art without undue experimentation.

In one embodiment, solutions for oral administration are prepared bydissolving the compound in any pharmaceutically acceptable solventcapable of dissolving a compound (e.g., ethanol or methylene chloride)to form a solution. An appropriate volume of a carrier which is asolution, such as beta-hydroxypropyl-cyclodextrin, is added to thesolution while stirring to form a pharmaceutically acceptable solutionfor oral administration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving a compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. The solvent can optionally be capable ofevaporating when the solution is dried under vacuum. An additionalcarrier can be added to the solution prior to drying, such asbeta-hydroxypropyl-cyclodextrin. The resulting solution is dried undervacuum to form a glass. The glass is then mixed with a binder to form apowder. The powder can be mixed with fillers or other conventionaltabletting agents and processed to form a tablet for oral administrationto a patient. The powder can also be added to any liquid carrier asdescribed above to form a solution, emulsion, suspension or the like fororal administration.

Emulsions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas LIPOSYN® II or LIPOSYN® III emulsions, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient.

Solutions for parenteral administration can be prepared by dissolving acompound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas beta-hydroxypropyl-cyclodextrin, is added to the solution whilestirring to form a pharmaceutically acceptable solution for parenteraladministration to a patient.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable concentration prior to use as is known in the art.

Still further encompassed by the disclosure are kits (e.g.,pharmaceutical packs). The kits provided may comprise a compound asdescribed herein and a container (e.g., a vial, ampule, bottle, syringe,and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical carrier for dilution or suspensionof the pharmaceutical composition or compound. In some embodiments, thepharmaceutical composition or compound provided in the container and thesecond container are combined to form one unit dosage form.

Optionally, instructions for use are additionally provided in such kitsof the disclosure. Such instructions may provide, generally, forexample, instructions for dosage and administration. In otherembodiments, instructions may further provide additional detail relatingto specialized instructions for particular containers and/or systems foradministration. Still further, instructions may provide specializedinstructions for use in conjunction and/or in combination with anadditional therapeutic agent.

3. Definitions

The term “ent-steroid” as used herein describes an organic compoundcontaining in its chemical nucleus the cyclopenta[a]phenanthrene ringsystem that is the mirror image of a naturally occurring steroid orsynthetic analogue derived from a naturally occurring steroid.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this disclosure include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As used herein, a “subject” to which administration is contemplatedincludes, but is not limited to, mammals, e.g., humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)), other primates (e.g., cynomolgus monkeys, rhesusmonkeys) and commercially relevant mammals such as cattle, pigs, horses,sheep, goats, cats, and/or dogs. In any aspect and/or embodiment of thedisclosure, the subject is a human.

As used herein, a “therapeutically effective amount” “an amountsufficient” or “sufficient amount” of a compound means the level, amountor concentration of the compound required for a desired biologicalresponse, e.g., analgesia.

The term “saturated” as used herein describes the state in which allavailable valence bonds of an atom (especially carbon) are attached toother atoms.

The term “unsaturated” as used herein describes the state in which notall available valence bonds along the alkyl chain are satisfied; in suchcompounds the extra bonds usually form double or triple bonds (chieflywith carbon).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁-4 alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₁₋₃, C₁₋₂, C₂₋₄, C₂₋₃ and C₃₋₄ alkyl, while“C₁₋₂₀ alkyl” is intended to encompass, for example, C₁, C₂, C₃, C₄,etc., as well as C₁₋₂₀, C₁₋₁₅, C₁₋₁₀, C₂₋₂₀, C₂₋₁₅, C₂₋₁₀, C₃₋₁₅, C₃₋₁₀,etc. alkyl.

As used herein, “alkyl” refers to a radical of a straight-chain orbranched saturated hydrocarbon group having from, in some embodiments, 1to 4 carbon atoms (“C₁₋₄ alkyl”), and in other embodiments 1 to 22carbon atoms (“C₁₋₂₂ alkyl”). In some embodiments, an alkyl group has 1to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl grouphas 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkylgroup has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkylgroup has 2 to 4 carbon atom (“C₂₋₄ alkyl”). In yet other embodiments,an alkyl group has 1 to 21 carbon atoms (“C₁₋₂₁ alkyl”), 1 to 20 carbonatoms (“C₁₋₂₀ alkyl”), 1 to 15 carbon atoms (“C₁₋₁₅ alkyl”), 1 to 10carbon atoms (“C₁₋₁₀ alkyl”), etc. Examples of such alkyl groups includemethyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), pentyl (C₅), and thelike.

As used herein, “alkenyl” or “alkene” refers to a radical of astraight-chain or branched hydrocarbon group having from, in someembodiments, 2 to 4 carbon atoms (“C₂₋₄ alkenyl”), and in otherembodiments 2 to 22 carbon atoms (“C₂₋₂₂ alkenyl”), and one or morecarbon-carbon double bonds. In some embodiments, an alkenyl group has 2to 3 carbon atoms (“C₂₋₃ alkenyl”). In some embodiments, an alkenylgroup has 2 carbon atoms (“C₂ alkenyl”). In yet other embodiments, analkenyl group has 2 to 21 carbon atoms (“C₂₋₂₁ alkenyl”), 2 to 20 carbonatoms (“C₂₋₂₀ alkenyl”), 2 to 15 carbon atoms (“C₂₋₁₅ alkenyl”), 2 to 10carbon atoms (“C₂₋₁₀ alkyl”), etc. The one or more carbon-carbon doublebonds can be internal (such as in 2-butenyl) or terminal (such as in1-butenyl). Examples of such alkenyl groups include ethenyl (C₂),1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄), 1-pentenyl (C₅), 2-pentenyl (C₅), and the like.

As used herein, “alkynyl” or “alkyne” refers to a radical of astraight-chain or branched hydrocarbon group having from 2 to 4 carbonatoms and one or more carbon-carbon triple bonds (“C₂₋₁₀ alkynyl”). Insome embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6,10, or 14 electrons shared in a cyclic array) having 6-14 ring carbonatoms and zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl).

As used herein, “alkoxy” refers to an alkyl, alkenyl, or alkynyl group,as defined herein, attached to an oxygen radical.

Alkyl, alkenyl, alkynyl, and aryl groups, as defined herein, aresubstituted or unsubstituted, also referred to herein as “optionallysubstituted”. In general, the term “substituted”, whether preceded bythe term “optionally” or not, means that at least one hydrogen presenton a group (e.g., a carbon or nitrogen atom) is replaced with apermissible substituent, e.g., a substituent which upon substitutionresults in a stable compound, e.g., a compound which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that result in theformation of a stable compound. The present disclosure contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this disclosure, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

As used herein, “spiroepoxide” refers to an epoxide formed from anexocyclic double bond on a ring.

Exemplary substituents include groups that contain a heteroatom (such asnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogenatom), halogen (e.g., chlorine, bromine, fluorine, or iodine), aheterocycle, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, spiroepoxide, keto, acyl, acyloxy, nitro, amino, amido, nitro,cyano, thiol, spirooxirane, ketals, acetals, esters and ethers.

EXAMPLES

The following Examples describe or illustrate various embodiments of thepresent disclosure. Other embodiments within the scope of the appendedclaims will be apparent to a skilled artisan considering thespecification or practice of the disclosure as described herein. It isintended that the specification, together with the Examples, beconsidered exemplary only, with the scope and spirit of the disclosurebeing indicated by the claims, which follow the Examples.*

Compound Chemistry

In accordance with the following methods and Examples, the followingcompounds were prepared for purposes of illustration.

General Methods.

Solvents were either used as purchased or dried and purified by standardmethodology. Extraction solvents were dried with anhydrous Na₂SO₄ andafter filtration, removed under reduced pressure on a rotary evaporator.Flash column chromatography was performed using silica gel (32-63 μm)purchased from Scientific Adsorbents (Atlanta, Ga.). Melting points weredetermined on a Kofler micro hot stage and are uncorrected. FT-IRspectra were recorded as films on a NaCl plate. NMR spectra wererecorded in CDCl₃ at ambient temperature at 300 or 400 MHz (¹H), 74 or100 MHz (¹³C).

In accordance with Scheme 1, the following compounds were prepared,using methods generally known in the art and as outlined below.

(8α,9β,10α,13α,14β)-Androst-4-ene-3,17-dione (1)

This compound was prepared as previously described. (Nilsson, K. R.;Zorumski, C. F.; Covey, D. F. Neurosteroid analogues. 6. The synthesisand GABA_(A) receptor pharmacology of enantiomers ofdehydroepiandrosterone sulfate, pregnenolone sulfate, and(3α,5β)-3-hydroxypregnan-20-one sulfate. J. Med. Chem. 1998, 41,2604-2613.)

(5β,8α,9β,10α,13α,14β)-Androst-3-en-17-one (2)

To a boiling solution of compound 1 (750 mg, 2.63 mmol) in glacial AcOH(40 mL), Zn dust (4.5 g) was added in several portions during a periodof 15 min and then heating was continued an additional 15 min. Thereaction was cooled, and the Zn dust was filtered, and the filtrate wascollected. The filter-cake was washed with AcOH and EtOAc. Solvents wereremoved from the combined filtrates and washings, water was added to theresidue and the product was extracted into EtOAc. The combined extractswere washed with aqueous NaHCO₃, brine, dried and solvents wereevaporated to give a white solid which is a mixture (2.3:1 by NMR) ofproduct 2 and the epimeric (5α)-3-ene product. The product mixture wascrystallized from hexanes to give pure product 2 (310 mg, 43%): mp122-125° C.; IR ν_(max) 3016, 2968, 2940, 2837, 2807, 1742, 1470, 1443,1376, 1251 cm⁻¹; ¹H NMR (CDCl₃) δ 5.60 (m, 1H), 5.29 (m, 1H), 2.44 (dd,1H, J=19.0 Hz, 9.0 Hz), 0.88 (s, 3H), 0.80 (s, 3H); ¹³C NMR (CDCl₃) δ221.3, 131.0 125.6, 53.5, 51.5, 47.9, 45.9, 35.8, 35.1, 35.0, 34.0,31.6, 30.9, 27.1, 23.4, 21.8, 20.3, 13.9, 11.8.

(3β,4β,5β,8α,9β,10α,13α,14β)-3,4-Epoxyandrostan-17-one (3)

Formic acid (0.42 mL) followed by 30% H₂O₂ (1 mL) was added to asolution of compound 2 (295 mg, 1.08 mmol) in stirred CH₂Cl₂ (15 mL) andstirring was continued at room temperature for 4 h. MeOH (10 mL) wasadded and after stirring for 3 min, 10% aqueous NaOH (5 mL) was addedand stirring was continued for 5 min. 10% HCl (6 mL) was then addeddropwise and stirring was continued for 3 min. The product was extractedinto CH₂Cl₂ (3×75 ml) and the combined organic extracts were dried andconcentrated to give an oil. After flash column chromatography (silicagel eluted with 20-30% EtOAc in hexanes) product 3 was obtained as awhite solid (300 mg, 84%): mp 148-150° C.; IR ν_(max) 2928, 2882, 2859,1740, 1472, 1446, 1405, 1373, 1251 cm⁻¹; ¹H NMR (CDCl₃) δ 3.09 (s, 1H),2.63 (d, 1H, J=3.9 Hz), 2.36 (dd, 1H, J=19.6 Hz, 9.0 Hz), 0.79 (s, 3H),0.73 (s, 3H); ¹³C NMR (CDCl₃) δ 220.7, 55.4, 52.5, 51.9, 51.0, 47.6,46.6, 35.6, 34.8, 34.0, 31.3, 30.5, 30.2, 26.3, 21.5, 21.1, 20.4, 13.7,13.3.

(3β,4α,5β,8α,9β,10α,13α,14β)-3-Hydroxy-4-methoxyandrostan-17-one (4,KK-117)

A drop of concentrated H₂SO₄ was added to stirred solution of compound 3(250 mg, 0.87 mmol) in MeOH (10 mL) and stirring was continued at roomtemperature for 3 h. The reaction was made alkaline by addition ofaqueous NaHCO₃ and the MeOH was removed on a rotary evaporator. Theresulting residue was diluted with water and extracted into EtOAc (3×75mL). The combined organic extracts were dried and concentrated to give asolid which was purified by flash column chromatography (silica geleluted with 35% EtOAc in hexanes) to give product 4 as a white solid(200 mg, 78%): mp 215-218° C.; [α]_(D) ²³ −99 (c 0.06, CHCl₃); IRν_(max) 3510, 2917, 2838, 1735, 1594, 1443, 1375, 1242 cm⁻¹; ¹H NMR(CDCl₃) δ 4.02 (br s, 1H), 3.35 (s, 3H), 3.04 (s, 1H), 2.44 (dd, 1H,J=19.0 Hz, 9.0 Hz), 0.98 (s, 3H), 0.86 (s, 3H), 0.62 (m, 1H); ¹³C NMR(CDCl₃) δ 221.5, 85.4, 66.1, 59.0, 55.2, 51.5, 47.8, 44.0, 36.2, 35.8,35.0, 31.8, 31.5, 31.1, 25.2, 25.0, 21.7, 19.6, 14.0, 13.8. Anal.(C₂₀H₃₂O₃): C, 74.96%; H, 10.06%. Found: C, 75.13%; H, 9.90%.

In accordance with Scheme 2, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-17-one (5)

The compound was prepared as previously described. (Katona, B. W.;Krishnan, K.; Cai, Z. Y.; Manion, B. D.; Benz, A.; Taylor, A.; Evers, A.S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. Neurosteroid analogues.12. Potent enhancement of GABA-mediated chloride currents at GABA_(A)receptors by ent-androgens. Eur. J. Med. Chem. 2008, 43, 107-113.)

(3β,5β,8α,9β,10α,13α,14α,17α)-16-(Phenylmethylene)-androstane-3,17-diolDiacetate (6)

Compound 5 (1.25 g, 4.5 mmol) and benzaldehyde (1.4 mL, 14 mmol) wereadded to KOH (700 mg) dissolved in EtOH (60 mL) and the reaction wasstirred at room temperature for 16 h. The reaction mixture was cooled to0° C. and CeCl₃.7 H₂O (7.45 g, 20 mmol) and NaBH₄ (756 mg, 20 mmol) wereadded, the reaction was allowed to warm to room temperature and stirringcontinued for 3 h. Glacial AcOH (7 mL) was added and the productextracted into EtOAc (3×150 mL). The combined extracts were dried andthe solvents removed to give an oil. The oil was dissolved in CH₂Cl₂ (30mL) and AcOAc (1.4 mL, 15 mmol), NEt₃ (4.2 ml, 30 mmol) and DMAP (200mg) were added and stirring was continued at room temperature for 4 h.Aqueous saturated NaHCO₃ was then added. After 1 h, the product wasextracted into CH₂Cl₂ (3×125 mL). The combined extracts were dried andsolvents removed to give an oil. The crude product was purified by flashcolumn chromatography (silica gel, eluted with 25-35% EtOAc in hexanes)to give product 6 as a colorless liquid containing benzyl acetate. Thebenzyl acetate was removed by applying high vacuum at 60° C. for 10 h,to give product 6 as a white solid (1.9 g, 91%): mp 162-164° C.; IRν_(max) 2932, 2855, 1735, 1492, 1447, 1371, 1237 cm⁻¹; ¹H NMR (CHCl₃) δ7.37-7.17 (m, 5H), 6.21 (d, 1H, J=2.4 Hz), 5.37 (s, 1H), 5.03 (s, 1H),2.68 (dd, 1H, J=16.8 Hz, 6.6 Hz), 2.21 (s, 3H), 2.07 (s, 3H), 0.83 (s,3H), 0.78 (s, 3H); ¹³C NMR (CHCl₃) δ 171.2, 170.7, 141.0, 137.6, 128.3(2×C), 128.2 (2×C), 126.4, 123.5, 84.6, 70.0, 54.1, 48.9, 42.9, 40.0,36.5, 35.9, 34.8, 32.8, 32.7, 31.5, 30.9, 28.1, 26.0, 21.5, 21.2, 20.3,12.3, 11.3.

(3β,5β,8α,9β,10α,13α,14β,17α)-3,17-Dihydroxyandrostan-16-one Diacetate(7)

Compound 7 was prepared from compound 5 by a multi-step procedurewithout isolation of intermediate compound 6. Compound 5 (115 mg, 0.35mmol) was dissolved in EtOH (20 mL), benzaldehyde (106 mg, 1.2 mmol) andKOH (50 mg) were added at room temperature. After 16 h, the reaction wascooled to 0° C. and CeCl₃.7 H₂O (740 mg, 2 mmol) and NaBH₄ (76 mg, 2mmol) were added. After stirring for 2 h, aqueous NH₄Cl was added andthe product extracted into EtOAc (3×50 mL) The combined extracts weredried and the solvents were removed on a rotary evaporator. The residuewas dissolved in CH₂Cl₂ (20 mL). Ac₂O (510 mg, 5.0 mmol) Et₃N (2.04 g,10.0 mmol) and DMAP (30 mg) were added and the reaction was stirred atroom temperature. After 1 h, water (30 mL) was added and crude product 6was extracted into CH₂Cl₂ (3×30 mL). The combined extracts were driedand the solvents removed. The crude product 6 was dissolved in MeOH (40mL) and EtOAc (20 mL) and cooled to −78° C. Ozone was bubbled throughthe solution for 30 min and excess ozone was removed with an O₂ streamfor 30 min. Me₂S (5 mL) was added at −78° C. and the reaction wasallowed to warm to room temperature. After 14 h, solvents were removedon a rotary evaporator and the residue was purified by flash columnchromatography (silica gel, eluted with 20% EtOAc in hexanes) to givecompound 7 was a white solid (110 mg, 82%, starting from compound 5) andhad: ¹H NMR (CDCl₃) δ 4.96 (m, 2H), 2.11 (s, 3H), 2.01 (s, 3H), 0.77 (s,6H); ¹³C NMR (CDCl₃) δ 211.0, 170.5, 170.2, 85.5, 69.7, 53.8, 45.2,41.6, 39.7, 36.2, 35.9, 35.8, 34.2, 32.6, 32.4, 31.4, 27.8, 25.8, 21.4,20.5, 19.7, 12.3, 11.2.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-16-one Acetate (8)

Freshly prepared Sm filings (1.5 mmol, 225 mg) were added to THF (10 mL)and I₂ (1.0 mmol, 254 mg) in THF (5 mL) was added at room temperature.The suspension was stirred under N₂. After 30 min, the mixture becamedeep blue indicating SmI₂ formation and stirring was continued foranother 30 min. Compound 7 (0.28 mmol, 110 mg) in THF/methanol (10/1, 11mL) was added. After 2 h, 10% aqueous Na₂CO₃ (60 mL) was added and theproduct was extracted into EtOAc (3×50 mL). The combined extracts werewashed with brine (2×20 mL) and dried. Solvents were removed and theresidue was purified by flash column chromatography (silica gel, elutedwith 20% EtOAc in hexanes) to give product 8 (48 mg, 51%) and a compoundin which the 16-ketone group had been reduced to a 16-hydroxyl group ofundetermined configuration (48 mg). Jones oxidation of the 16-hydroxylgroup gave additional compound 8 (40 mg, 43%): ¹H NMR (CDCl₃) δ 5.00 (brs, 1H), 2.03 (s, 3H), 0.86 (s, 3H), 0.81 (s, 3H); ¹³C NMR (CDCl₃) δ218.7, 170.6, 69.9, 55.8, 54.1, 51.7, 39.9, 39.1, 38.1, 35.9, 34.8,32.7, 32.5, 32.1, 28.0, 26.0, 21.5, 20.3, 18.0, 11.3.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-16-one (9, MQ-35)

Compound 8 (88 mg, 0.27 mmol) was dissolved in methanol (10 mL) andwater (0.5 mL) and K₂CO₃ (5 mmol, 680 mg) were added. The reaction wasrefluxed for 2 h, cooled to room temperature, water (30 mL) was addedand the product was extracted into EtOAc (50 mL×3). The combinedextracts were dried, filtered, and the solvent removed. The residue waspurified by flash column chromatography (silica gel, eluted with 25-40%EtOAc in hexanes) to give product 9 (72 mg, 93%) as a white solid: mp152-153° C.; [α]_(D) ²³ +156.8 (c 0.25, CHCl₃); IR ν_(max) 3435, 1737cm⁻¹; ¹H NMR (CDCl₃) δ 4.06 (m, 1H), 0.87 (s, 3H), 0.81 (s, 3H); ¹³C NMR(CDCl₃) δ 219.0, 66.4, 55.9, 54.2, 51.7, 39.3, 39.2, 39.0, 38.2, 36.3,35.8, 34.9, 32.2, 31.9, 28.9, 28.3, 20.3, 18.1, 11.2. Anal. (C₁₉H₃₀O₂):C, 78.57%; H, 10.41%. found: C, 78.36%; H, 10.58%.

Compounds 25 (KK-97), 26 (KK-102), 27 (KK-103) and 28 (KK-122) were alsoprepared by the synthetic sequence shown in Scheme 2. Compound 25 wasprepared by the following compound sequence: 10→13→17→21→25. Compound 26was prepared by the following compound sequence: 11→14→18→22→26.Compound 27 was prepared by the following compound sequence:12→15→19→23→27. Compound 28 was prepared by the following compoundsequence: 4→16→20→24→28.

(3β,5α,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-17-one (10)

The 5α-reduced compound 10 was prepared from ent-testosterone aspreviously described. (Katona, B. W.; Krishnan, K.; Cai, Z. Y.; Manion,B. D.; Benz, A.; Taylor, A.; Evers, A. S.; Zorumski, C. F.; Mennerick,S.; Covey, D. F. Neurosteroid analogues. 12. Potent enhancement ofGABA-mediated chloride currents at GABA_(A) receptors by ent-androgens.Eur. J. Med. Chem. 2008, 43, 107-113.)

(3β,5α,8α,9β,10α,13α,14β)-3-Hydroxyestran-17-one (11)

The 5α-reduced compound 11 was prepared from the known compound(8α,9β,10α,13α,14β,17α)-17-hydroxyestr-4-en-3-one (Green, P. S.; Yang,S. H.; Nilsson, K. R.; Kumar, A. S.; Covey, D. F.; Simpkins, J. W. Thenonfeminizing enantiomer of 17β-estradiol exerts protective effects inneuronal cultures and a rat model of cerebral ischemia. Endocrinology2001, 142, 400-406.) using the methods reported previously for thepreparation of 5α-reduced compound 10 from ent-testosterone. (Katona, B.W.; Krishnan, K.; Cai, Z. Y.; Manion, B. D.; Benz, A.; Taylor, A.;Evers, A. S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. Neurosteroidanalogues. 12. Potent enhancement of GABA-mediated chloride currents atGABA_(A) receptors by ent-androgens. Eur. J. Med. Chem. 2008, 43,107-113.) Compound 11 was a white solid and had: mp 161-163° C.; [α]_(D)²³ −117.4 (c 0.55, CHCl₃); IR ν_(max) 3401, 2924, 2859, 1738, 1453, 1375cm⁻¹; ¹H NMR (CDCl₃) δ 3.64 (m, 1H), 0.87 (s, 3H); ¹³C NMR (CDCl₃) δ221.5, 71.5, 50.5, 47.9, 41.2, 39.9, 38.6, 36.3, 35.9, 35.6, 31.6, 31.3,29.6, 25.9, 25.0, 24.9, 21.6, 13.8. Anal. (C₁₈H₂₈O₂): C, 78.21%; H,10.21%. Found: C, 78.12%; H, 9.98%.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyestran-17-one (12, KK-18)

The 5β-reduced compound 12 was prepared from the known compound(8α,9β,10α,13α,14β,17α)-17-hydroxyestr-4-en-3-one (Green, P. S.; Yang,S. H.; Nilsson, K. R.; Kumar, A. S.; Covey, D. F.; Simpkins, J. W. Thenonfeminizing enantiomer of 17β-estradiol exerts protective effects inneuronal cultures and a rat model of cerebral ischemia. Endocrinology2001, 142, 400-406.) using the methods reported previously for thepreparation of 5β-reduced compound 5 from ent-testosterone. (Katona, B.W.; Krishnan, K.; Cai, Z. Y.; Manion, B. D.; Benz, A.; Taylor, A.;Evers, A. S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. Neurosteroidanalogues. 12. Potent enhancement of GABA-mediated chloride currents atGABA_(A) receptors by ent-androgens. Eur. J. Med. Chem. 2008, 43,107-113.) Compound 12 was a white solid and had: mp 158-160° C.; [α]_(D)²³ −108.5 (c 0.24 CHCl₃); IR ν_(max) 3517, 2913, 2948, 2859, 1721, 1662,1445, 1379, 1337, 1300, 1268 cm⁻¹; ¹H NMR (CDCl₃) δ 4.10 (br s, 1H),0.88 (s, 3H); ¹³C NMR (CDCl₃) δ 221.7, 66.3 50.6, 48.2, 47.9, 47.0,40.7, 40.5, 35.9, 35.8, 33.3, 32.9, 31.5, 29.8, 24.9, 23.7, 21.6, 13.8.HRMS (FAB) m/z Calcd for C₁₈H₂₈O₂Na: 299.1987. Found, 299.1989.

(3β,5α,8α,9β,10α,13α,14β)-16-(Phenylmethylene)-androstane-3,17-diolDiacetate (13)

Compound 13 was prepared as a white solid (205 mg, 92%) froment-etiocholanolone (10) (Katona, B. W.; Krishnan, K.; Cai, Z. Y.;Manion, B. D.; Benz, A.; Taylor, A.; Evers, A. S.; Zorumski, C. F.;Mennerick, S.; Covey, D. F. Neurosteroid analogues. 12. Potentenhancement of GABA-mediated chloride currents at GABA_(A) receptors byent-androgens. Eur. J. Med. Chem. 2008, 43, 107-113.) using theprocedure described for the preparation of compound 6. Compound 13 had:mp 96-99° C.; IR ν_(max) 3032, 2866, 2935, 1738, 1493, 1449, 1380, 1363,1241 cm⁻¹; ¹H NMR (CDCl₃) δ 7.37-7.18 (m, 5H), 6.21 (bs, 1H), 5.38 (s,1H), 4.74 (m, 1H), 2.67 (dd, 1H, J=13 Hz, 7 Hz), 2.21 (s, 3H), 2.04 (s,3H), 0.96 (s, 3H), 0.77 (s, 3H); ¹³C NMR (CDCl₃) δ 171.2, 170.7, 141.0,137.6, 128.3, 128.2, 126.5, 123.6, 84.5, 74.2, 48.9, 43.0, 41.8, 40.5,36.6, 35.2, 35.0, 34.7, 32.2, 30.9, 26.8, 26.6, 26.0, 23.3, 21.4, 21.2,20.3, 12.2. Anal. (C₃₀H₄₀O₄): C, 77.55%; H, 8.68%. Found: C, 77.60%; H,8.36%.

(3β,5α,8α,9β,10α,13α,14β,17α)-19-Nor-16-(phenylmethylene)-androstane-3,17-diolDiacetate (14)

Compound 14 was prepared as a white solid (700 mg, 74%) froment-19-noretiocholanolone (11) using the procedure described for thepreparation of compound 6. Compound 14 had: mp 133-135° C.; IR ν_(max)2920, 2870, 1737, 1736, 1448, 1370, 1239 cm⁻¹; ¹H NMR (CDCl₃) δ7.40-7.18 (m, 5H), 6.21 (d, 1H, J=2.5 Hz), 5.39 (s, 1H), 4.75 (m, 1H),2.67 (dd, 1H, J=16.4 Hz, 7.0 Hz), 2.21 (s, 3H), 2.04 (s, 3H), 0.78 (s,3H); ¹³C NMR (CDCl₃) δ 171.14, 170.61, 140.90, 137.55, 128.26, 128.23,126.45, 123.57, 84.61, 74.07, 47.90, 43.09, 41.03, 39.78, 38.37, 36.47,35.35, 32.24, 31.18, 30.78, 25.74, 25.68, 25.07, 21.43, 21.16, 12.20.Anal. (C₂₈H₃₈O₄): C, 77.30%; H, 8.57%. Found: C, 77.19%; H, 8.53%.

(3β,5β,8α,9β,10α,13α,14α,17α)-19-Nor-16-(phenylmethylene)-androstane-3,17-diolDiacetate (15)

Compound 15 (670 mg, 91%) was prepared as an oil from compoundent-19-norandrosterone (12) using the procedure described for thepreparation of compound 6. Compound 12 had: IR ν_(max) 2919, 2862, 1738,1600, 1492, 1446, 1370, 1240 cm⁻¹; ¹H NMR (CDCl₃) δ 7.40-7.10 (m, 5H),6.24 (b s, 1H), 5.40 (b s 1H), 5.07 (b s, 1H), 2.69 (dd, 1H, J=16.7 Hz,6.3 Hz), 2.23 (s, 3H), 2.07 (s, 3H), 0.81 (s, 3H); ¹³C (CDCl₃) NMR δ171.0, 170.6, 140.9, 137.5, 128.2 (4×C), 126.4, 123.5, 84.5, 69.7, 48.0,47.8, 46.5, 42.9, 40.4, 37.4, 36.6, 36.4, 33.2, 30.7, 30.4, 29.9, 25.0,24.2, 21.4, 21.1, 12.1. Anal. (C₂₉H₃₈O₄): C, 77.30%; H, 8.50%. Found: C,77.55%; H, 8.26%.

(3β,4α,5β,8α,9β,10α,13α,14β)-4-Methoxy-16-(phenylmethylene)-androstane-3,17-diolDiacetate (16)

Compound 16 (300 mg, 97%) was prepared as a white solid from compound 4using the procedure described for the preparation of compound 6.Compound 13 had: mp 150-152° C.; IR ν_(max) 2935, 2859, 1738, 1599,1492, 1448, 1371, 1241 cm⁻¹; ¹H NMR (CDCl₃) δ 7.30-7.08 (m, 5H), 6.13(d, 1H, J=2.2 Hz), 5.28 (s, 1H), 4.97 (d, 1H, J=2.3 Hz), 3.30 (s, 3H),3.22 (s, 1H), 2.60 (m, 1H), 2.12 (s, 3H), 2.00 (s, 3H), 0.90 (s, 3H),0.69 (s, 3H); ¹³C NMR (CDCl₃) δ 171.2, 170.4, 141.0, 137.6, 128.3 (2×C),128.2 (2×C), 126.4, 123.5, 84.6, 82.5, 68.6, 58.9, 55.0, 49.0, 45.0,42.9, 36.4, 35.9, 34.8, 32.5, 31.8, 30.9, 25.0, 22.0, 21.4, 21.2, 19.9,14.0, 12.3.

(3β,5α,8α,9β,10α,13α,14β,17α)-3,17-Dihydroxyandrostan-16-one Diacetate(17)

Compound 17 was prepared as a white solid (148 mg, 90%) from compound 13using the ozonolysis reaction described within the multi-step procedurefor the preparation of compound 7. Compound 17 had: mp 164-166° C.; IRν_(max) 2937, 2868, 1762, 1739, 1451, 1365, 1240 cm⁻¹; ¹H NMR (CDCl₃) δ5.30 (s, 1H), 5.02 (m, 1H), 2.40-0.90 (m), 2.17 (s, 3H), 2.04 (s, 3H),0.97 (s, 3H), 0.82 (s, 3H); ¹³C NMR (CDCl₃) δ 211.0, 170.6, 170.3, 85.6,73.9, 45.3, 41.7, 41.5, 40.4, 36.4, 36.0, 34.7, 34.6, 32.1, 26.5, 26.1,23.1, 21.4, 20.6, 19.8, 12.3. HRMS (FAB) m/z Calcd for C₂₃H₃₄O₅Na:413.2304. Found: 413.2309.

(3β,5α,8α,9β,10α,13α,14β,17α)-19-Nor-3,17-dihydroxyandrostan-16-oneDiacetate (18)

Compound 18 was prepared as a white solid (540 mg, 95%) from compound 14using the ozonolysis reaction described within the multi-step procedurefor the preparation of compound 7. Compound 18 had: mp 144-146° C.; IRν_(max) 2922, 2868, 1761, 1742, 1454, 1371, 1239 cm⁻¹; ¹H NMR (CDCl₃) δ4.94 (s, 1H), 4.65 (m), 2.23 (dd, 1H, J=18.4 Hz, 7.4 Hz), 2.08 (s, 3H),1.94 (s, 3H), 0.75 (s, 3H); ¹³C NMR (CDCl₃) δ 210.6, 170.2, 170.0, 85.5,73.6, 44.1, 41.6, 40.1, 39.5, 38.5, 36.0, 35.7, 35.0, 31.9, 30.8, 25.6,25.4, 25.2, 24.4, 21.1, 20.4, 12.1. Anal. (C₂₂H₃₂O₅): C, 70.18%; H,8.57%. Found: C, 70.44%; H, 8.57%.

(3β,5β,8α,9β,10α,13α,14β,17α)-19-Nor-3,17-dihydroxyandrostan-16-oneDiacetate (19)

Compound 19 (530 mg, 98%) was prepared as a white solid from compound 15using the ozonolysis reaction described within the multi-step procedurefor the preparation of compound 7. Compound 19 had: mp 116-118° C.; IRν_(max) 2919, 2861, 1763, 1736, 1445, 1371, 1239, 1216 cm⁻¹; ¹H NMR(CDCl₃) δ 4.91 (br s, 1H), 4.89 (s, 1H), 2.19 (dd, 1H, J=18.7 Hz, 7.7Hz), 2.03 (s, 3H), 1.92 (s, 3H), 0.71 (s, 3H); ¹³C NMR (CDCl₃) δ 210.6,170.1, 169.9, 85.4, 69.3, 47.4, 46.1, 44.1, 41.5, 39.5, 37.1, 36.2,35.9, 35.6, 32.8, 30.3, 29.6, 24.3, 23.7, 21.1, 20.3, 12.0. Anal.(C₂₂H₃₂O₅): C, 70.18%; H, 8.57%. Found: C, 70.30%; H, 8.59%.

(3β,4α,5β,8α,9β,10α,13α,14β,17α)-3,17-Dihydroxy-4-methoxyandrostan-16-oneDiacetate (20)

Compound 20 (205 mg, 87%) was prepared as a white solid from compound 16using the ozonolysis reaction described within the multi-step procedurefor the preparation of compound 7. Compound 20 had: mp 158-160° C.; IRν_(max) 2928, 1762, 1742, 1449, 1372, 1240 cm⁻¹; ¹H NMR (CDCl₃) δ 5.02(d, 1H, J=2.0 Hz), 4.97 (s, 1H), 3.34 (s, 3H), 3.01 (br s, 1H), 2.13 (s,3H), 2.05 (s, 3H), 0.96 (s, 3H), 0.79 (s, 3H); ¹³C NMR (CDCl₃) δ 211.0,170.3 (2×C), 85.6, 82.2, 68.5, 58.8, 54.8, 45.3, 44.8, 41.6, 36.2, 36.0,35.8, 34.3, 32.3, 31.8, 24.8, 21.9, 21.3, 20.6, 19.4, 13.9, 12.4.

(3β,5α,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-16-one Acetate (21)

Compound 21 was prepared as a colorless liquid (100 mg, 83%) fromcompound 17 using the procedure described for the preparation ofcompound 8. Compound 21 had: IR ν_(max) 2867, 2932, 1739, 1451, 1408,1382, 1363, 1243 cm⁻¹; ¹H NMR (CDCl₃) δ 4.72 (m, 1H), 2.02 (s, 3H), 0.96(s, 3H), 0.86 (s, 3H); ¹³C NMR (CDCl₃) δ 218.6, 170.6, 74.0, 55.9, 51.7,41.6, 40.5, 39.2, 39.2, 38.3, 35.2, 34.7, 32.1, 26.5, 23.2, 21.4, 20.3,18.0. Anal. (C₂₁H₃₂O₃): C, 75.86%; H, 9.70%. Found: C, 75.75%; H, 9.74%.

(3β,5α,8α,9β,10α,13α,14β)-19-Nor-3-hydroxyandrostan-16-one Acetate (22)

Compound 22 was prepared as a white amorphous solid (380 mg, 97%) fromcompound 118 using the procedure described for the preparation ofcompound 8. Compound 22 had: mp 107-110° C.; IR ν_(max) 2919, 2869,1744, 1454, 1408, 1366, 1243 cm⁻¹; ¹H NMR (CDCl₃) δ 4.69 (m, 1H), 1.98(s, 3H), 0.84 (s, 3H); ¹³C NMR (CDCl₃) δ 218.1, 170.3, 73.8, 55.9, 50.7,40.9, 39.7, 39.1, 38.9, 38.1, 35.1, 32.1, 31.1, 31.0, 26.3, 25.6, 25.3,25.0, 21.2, 18.0. HRMS (FAB) m/z Calcd for C₂₀H₃₁O₃: 319.2273. Found:319.2272.

(3β,5β,8α,9β,10α,13α,14β)-19-Nor-3-hydroxyandrostan-16-one Acetate (23)

Compound 23 (290 mg, 70%) was prepared as a colorless oil from compound19 using the procedure described for the preparation of compound 8.Compound 23 had: IR ν_(max) 2918, 2862, 1737, 1444, 1408, 1378, 1244,1214 cm⁻¹; ¹H NMR (CDCl₃) δ 4.97 (b s, 1H), 1.97 (s, 3H), 0.82 (s, 3H);¹³C NMR (CDCl₃) δ 218.1, 170.3, 69.6, 55.8, 50.8, 47.8, 46.5, 40.4,39.0, 38.9, 38.0, 37.3, 36.5, 36.5, 33.1, 31.0, 29.8, 25.0, 23.3, 21.2,17.9. Anal. (C₂₀H₃₀O₃): C, 75.43%; H, 9.50%. Found: C, 75.17%; H, 9.39%.

(3β,4α,5β,8α,9β,10α,13α,14β)-3-Hydroxy-4-Methoxyandrostan-16-one Acetate(24)

Compound 24 (72 mg, 84%) was prepared as a white solid from compound 20using the procedure described for the preparation of compound 8.Compound 24 had: mp 159-161° C.; IR ν_(max) 2944, 2861, 1733, 1449,1407, 1380, 1244, 1216 cm⁻¹; ¹H NMR (CDCl₃) δ 5.03 (d, 1H, J=1.6 Hz),3.36 (s, 3H), 3.03 (br s, 1H), 2.07 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H);¹³C NMR (CDCl₃) δ 218.8, 170.4, 82.4, 68.6, 58.9, 55.8, 55.0, 51.8,44.9, 39.3, 39.1, 38.1, 35.9, 34.9, 32.4, 32.4, 24.9, 22.0, 21.4, 19.9,18.1, 14.0.

(3β,5α,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-16-one (25, KK-97)

Compound 25 was prepared from compound 21 using the procedure describedfor the preparation of compound 9. Flash column chromatography (silicagel, eluted with 25-40% EtOAc in hexanes) gave product 25 as a whitesolid (70 mg, 89%): mp 132-134° C.; [α]_(D) ²³ +177.44 (c 0.1, CHCl₃);IR ν_(max) 3401, 2928, 2860, 1743, 1450, 1380 cm⁻¹; ¹H NMR (CDCl₃) δ3.63 (1H, m), 0.95 (s, 3H), 0.94 (s, 3H); ¹³C NMR (CDCl₃) δ 218.9, 71.5,55.9, 51.7, 41.8, 40.5, 39.3, 39.2, 38.3, 36.3, 35.2, 35.0, 34.7, 30.4,26.9, 26.7, 23.2, 20.3, 18.0. HRMS (EI) m/z Calcd for C₁₉H₂₁O₂:291.2324. Found: 291.2323.

(3β,5α,8α,9β,10α,13α,14β)-19-Norandrostan-16-one (26, KK-102)

Compound 26 was prepared from compound 22 using the procedure describedfor the preparation of compound 9. Flash column chromatography (silicagel, eluted with 25-40% EtOAc in hexanes) gave product 26 as a whitesolid (276 mg, 89%): mp 139-142° C.; [α]_(D) ²³ +160 (c 0.1, CHCl₃); IRν_(max) 3401, 2922, 2859, 1744, 1453, 1407, 1280 cm⁻¹; ¹H NMR (CDCl₃) δ3.57 (m, 1H), 2.53 (bs 1H, OH), 0.81 (s, 3H); ¹³C NMR (CDCl₃) δ 218.7,71.1, 55.9, 50.6, 40.9, 39.8, 39.1, 38.9, 38.4, 38.0, 36.1, 35.2, 31.1,29.3, 26.4, 25.5, 24.9, 17.9. Anal. (C₁₈H₂₈O₂): C, 78.21%; H, 10.21%.Found: C, 78.06%; H, 10.11%.

(3β,5β,8α,9β,10α,13α,14β)-19-Norandrostan-16-one (27, KK-103)

Compound 24 (207 mg, 98%) was prepared from compound 23 using theprocedure described for the preparation of compound 9. Flash columnchromatography (silica gel, eluted with 25-40% EtOAc in hexanes) gaveproduct 27 as a white solid: mp 160-162° C.; [α]_(D) ²³ +162.0 (c 0.22,CHCl₃); IR ν_(max) 3401, 2915, 2861, 1743 cm⁻¹; ¹H NMR (CDCl₃) δ 4.08(br s, 1H), 0.87 (s, 3H); ¹³C NMR (CDCl₃) δ 218.8, 66.3, 56.0, 50.9,48.0, 47.0, 40.53, 40.47, 39.2, 39.1, 38.1, 35.8, 33.4, 32.9, 31.2,25.1, 23.4, 18.1. Anal. (C₁₈H₂₈O₂): C, 78.21%; H, 10.21%. Found: C,78.40%; H, 10.15%.

(3β,4α,5β,8α,9β,10α,3α,14β)-3-Hydroxy-4-methoxyandrostan-16-one (28,KK-122)

Compound 28 (50 mg, 94%) was prepared from compound 24 using theprocedure described for the preparation of compound 9. Flash columnchromatography (silica gel, eluted with 25-40% EtOAc in hexanes) gaveproduct 24 as a white solid: mp 198-200° C.; [α]_(D) ²³ +152 (c 0.2,CHCl₃); IR ν_(max) 3458, 1725 cm⁻¹; ¹H NMR (CDCl₃) δ 4.01 (br s, 1H),3.34 (s, 3H), 3.02 (d, 1H, J=1.1 Hz), 0.98 (s, 3H), 0.87 (s, 3H); ¹³CNMR δ 219.0, 85.4, 66.2, 59.0, 55.9, 55.1, 51.8, 43.9, 39.3, 39.3, 38.1,36.2, 34.9, 32.6, 31.6, 25.2, 25.0, 19.9, 18.1, 14.0. Anal. (C₂₀H₃₂O₃):C, 74.96%; H, 10.06%. Found: C, 75.07%; H, 9.96%.

In accordance with Scheme 3, the following compounds were prepared,using methods generally known in the art and as outlined below.

(5β,8α,9β,10α,13α,14β,17α)-17-Hydroxyandrostan-3-one (29)

This compound was prepared as previously described. (Hu, Y. F.; Wittmer,L. L.; Kalkbrenner, M.; Evers, A. S.; Zorumski, C. F.; Covey, D. F.Neurosteroid analogues. Part 5. Enantiomers of neuroactive steroids andbenz[e]indenes: total synthesis, electrophysiological effects onGABA_(A) receptor function and anesthetic actions in tadpoles. J. Chem.Soc. Perkin Trans. 1 1997, 3665-3671.)

(5β,8α,9β,10α,13α,14β,17α)-17-[[(4-Phenylmethyl)sulfonyl]oxy]-androstan-3-one(30)

Compound 29 (1.8 g, 6.54 mmol), p-TsCl (2.5 g, 13.08 mmol) and pyridine(60 mL) were heated at 40° C. for 18 h. The reaction mixture was cooledand poured into a beaker containing crushed ice. The mixture wasextracted with CH₂Cl₂ (3×100 mL) and the combined extracts were washedwith 1N HCl to remove the pyridine, washed with brine, dried and solventremoved. The crude product was purified by flash column chromatography(silica gel, eluted with 10% EtOAc in CH₂Cl₂) to give product 30 as awhite crystalline solid (2.65 g, 91%). mp 180-182° C.; IR ν_(max) 2917,2851, 1710, 1598, 1449, 1415, 1361, 1253, 1217 cm⁻¹; ¹H NMR (CDCl₃) δ7.77 (d, 2H, J=7.8 Hz), 7.32 (d, 2H, J=7.8 Hz), 4.24 (t, 1H, J=8.2 Hz),2.44 (s, 3H), 0.98 (s, 3H), 0.80 (s, 3H); ¹³C NMR (CDCl₃) δ 211.7,144.4, 134.1, 129.6 (2×C), 127.76 (2×C), 89.8, 53.5, 49.7, 46.5, 44.5,43.0, 38.4, 38.0, 36.0, 35.6, 35.0, 31.0, 28.6, 27.6, 23.2, 21.6, 21.6,20.7, 11.8. 11.4.

(3β,5β,8α,9β,10α,13α,14β,17α)-17-[[(4-Phenylmethyl)sulfonyl]oxy]-androstan-3-ol(31)

Compound 30 (2.8 g, 6.3 mmol) was dissolved in THF (50 mL), cooled to−78° C. and K-selectride in THF (1 M, 7.2 mL, 7.2 mmol, 1.2 eq) wasadded dropwise. Stirring at −78° C. was continued for 2 h. Aqueous NaOH(3 M, 20 mL) and then 30% H₂O₂ (20 mL) were added and the reaction waswarmed to room temperature and stirred for 2 h. Water (150 mL) was addedand the product was extracted into EtOAc. The combined EtOAc extractswere dried and the solvents removed to give an oil which was purified byflash column chromatography (silica gel, eluted with 10% EtOAc inCH₂Cl₂) to give product 31 (2 g, 71%): mp 186-188° C.; IR ν_(max) 3400,2918, 2850, 1599, 1446, 1355 cm⁻¹; ¹H NMR (CDCl₃) δ 7.77 (d, 2H, J=7.1Hz), 7.32 (d, 2H, J=7.1 Hz), 4.24 (t, 1H, J=7.8 Hz), 4.03 (d, 1H, J=2.3Hz) 2.44 (s, 3H), 0.78 (s, 3H), 0.75 (s, 3H); ¹³C NMR (CDCl₃) δ 144.1,134.2, 129.6 (2×C), 127.8 (2×C), 90.1, 66.4, 66.3, 54.1, 50.0, 43.0,39.0, 36.1, 35.7, 35.1, 32.1, 31.3, 28.9, 28.2, 27.6, 23.2, 21.6, 20.0,11.8, 11.1.

(3β,5β,8α,9β,10α,14β)-17-Methylandrost-14(17)-en-3-ol (32)

MeMgBr (3 M in Et₂O, 5 mL) was added to refluxing toluene (80 mL)containing dissolved compound 31 (1.34 g, 3 mmol) and refluxing wascontinued for 1 h under N₂. The reaction was cooled, acidified with 1NHCl and extracted with CH₂Cl₂. The combined extracts were washed withbrine, dried and concentrated to give an oil. The oil was dissolved inMeOH (20 mL) and 5 M HCl (prepared from concentrated HCl diluted withMeOH) was added and the reaction was stirred at room temperature for 15h. The reaction was made basic by the addition of aqueous NaHCO₃ and theMeOH was removed. The aqueous residue was diluted further with water andthe product extracted into EtOAc. The combined extracts were dried andconcentrated to give an oil, which was purified by flash columnchromatography (silica gel, eluted with 15-35% EtOAc in hexanes) to giveproduct 32 as a colorless oil (750 mg, 91%): IR ν_(max) 3337, 2920,2856, 1444, 1359, 1255 cm⁻¹; ¹H NMR (CDCl₃) δ 4.02 (br s, 1H), 1.58 (s,3H), 0.68 (s, 3H); ¹³C NMR (CDCl₃) δ 136.5, 127.4, 66.4, 53.9, 52.3,45.3, 38.7, 37.1, 36.1, 35.8, 32.3, 32.2, 28.9, 28.3, 28.1, 25.6, 25.2,13.4, 11.1.

(3β,5β,8α,9β,10α,14β)-3-(Methoxymethoxy)-17-methylandrost-14(17)-ene(33)

Compound 32 (823 mg, 3 mmol) was dissolved CH₂Cl₂ (80 mL) and cooled to0° C. (i-Pr)₂EtN (2.6 mL, 15 mmol) and ClCH₂OMe (0.76 ml, 10 mmol) wereadded and the reaction was stirred at room temperature for 6 h. Thereaction mixture was made basic by adding aqueous NaHCO₃ solution andthe product extracted into CH₂Cl₂. The combined extracts were washedwith brine, dried and solvent removed to give a viscous liquid. Thecrude product was purified by flash column chromatography (silica gel,eluted with 10-15% EtOAc in hexanes) to give product 33 as a colorlessliquid (960 mg, 90%): IR ν_(max) 2924, 2857, 1445, 1368, 1302, 1213cm⁻¹; ¹H NMR (CDCl₃) δ 4.57 (s, 2H), 3.75 (s, 1H), 3.28 (s, 3H), 1.51(s, 3H), 0.64 (s, 3H); ¹³C NMR (CDCl₃) δ 136.4, 127.1, 94.3, 71.4, 54.8,53.8, 52.2, 45.3, 39.2, 37.0, 35.8, 33.5, 32.8, 32.2, 28.3, 28.0, 26.2,25.6, 25.2, 13.2, 11.2.

(1R,4aR,4bR,7S,8aR,10aS)-7-(Methoxymethoxy)docecahydro-4b-methyl-1(3-oxobutyl-2(1H)-phenanthrenone(34)

Compound 33 (2.38 g, 7.5 mmol) was dissolved in CH₂Cl₂ (100 mL) andcooled to −78° C. O₃ was passed through the solution until it remainedblue for 20 min and then O₂ was passed through the solution until itbecame colorless. The reaction was warmed to 0° C., AcOH (30 mL) wasadded and the CH₂Cl₂ removed on a rotary evaporator. Additional AcOH (15mL) and Zn dust (6 g) were added and the reaction was stirred at roomtemperature for 3 h to decompose the ozonide intermediate. The Zn wasremoved by filtration through Celite and the Celite was washed withEtOAc. The combined filtrate and washings were combined and the volatilesolvents removed to leave the product in AcOH. The AcOH was carefullyneutralized with aqueous NaHCO₃ and the product extracted into EtOAc.The combined extracts were dried and solvent removed to leave the crudeproduct as an oil which was purified by flash column chromatography(silica gel, eluted with 20-35% EtOAc in hexanes) to give product 34(1.7 g, 65%) as a liquid: IR ν_(max) 2928, 1712, 1447, 1367, 1213 cm⁻¹;¹H NMR (CDCl₃) δ 4.57 (s, 2H), 3.75 (s, 1H), 3.28 (s, 3H), 2.03 (s, 3H),0.65 (s, 3H); ¹³C NMR (CDCl₃) δ 212.2, 208.7, 94.3, 71.2, 54.9, 54.6,52.1, 42.3, 41.7, 40.8, 38.7, 36.0, 33.0, 32.6, 32.0, 29.6, 28.0, 26.2,26.1, 19.2, 10.9.

(3β,5β,8α,9β,10α,14β)-3-(Methoxymethoxy)-D-Homo-18-norandrost-13(17a)-en-17-oneAcetate (35)

Compound 34 (1.55 g, 4.43 mmol) was dissolved in MeOH (15 mL) and water(1.5 mL), 10% methanolic NaOH (12 mL) was added and the reaction wasstirred at room temperature for 1 h. The reaction was then acidifiedwith 3N HCl and the product extracted into CH₂Cl₂. The combined extractswere washed with aq. NaHCO₃, brine, dried and the solvents were removed.The crude product was purified by flash column chromatography (silicagel, eluted with 30-40% ethyl acetate in hexanes) to give product 35 asa white solid. (1.10 g, 75%): mp 98-100° C.; IR ν_(max) 2926, 1674,1622, 1449, 1364, 1259, 1209 cm⁻¹; ¹H NMR (CDCl₃) δ 5.68 (s, 1H), 4.55(s, 2H), 3.74 (s, 1H), 3.27 (s, 3H), 0.63 (s, 3H); ¹³C NMR (CDCl₃) δ199.5, 166.4, 123.7, 94.3, 71.1, 54.9, 52.0, 43.6, 43.0, 38.6, 36.2,35.8, 35.8, 35.7, 33.1, 32.5, 31.1, 27.9, 26.1, 25.9, 25.3, 10.9.

(3β,5β,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-D-Homo-18-norandrostan-17-one(36)

Liquid NH₃ (250 mL) was condensed in a 3-necked 500 mL round bottomflask fitted with a Dewar condenser containing Dry Ice/acetone and anoverhead stirrer and then placed in a cold bath at −78° C. Li (140 mg,20 mmol) was added and stirring continued for 30 min during which timethe solution became deep blue. THF (80 mL) was added and after 10 min,compound 35 (942 mg, 2.7 mmol) dissolved in THF (40 mL) was added andstirring continued for 1 h. Solid NH₄Cl (5 g) was added and the solutionbecame colorless. The reaction was allowed to warm to room temperatureand the liq. NH₃ was allowed to evaporate. Water was added and theproduct extracted into EtOAc. The combined extracts were washed withbrine, dried and solvent removed to give a yellow solid which waspurified by flash column chromatography (silica gel, eluted with 30%EtOAc in hexanes) to give product 36 as a white solid (650 mg, 72%): mp85-87° C.; IR ν_(max) 2919, 2859, 1717, 1445, 1366, 1322, 1206, 1209cm⁻¹; ¹H NMR (CDCl₃) δ 4.65 (s, 2H), 3.82 (s, 1H), 3.36 (s, 3H), 0.72(s, 3H); ¹³C NMR (CDCl₃) δ 211.9, 94.5, 71.4, 55.1, 52.9, 48.6, 47.4,43.3, 41.3, 40.8, 39.1, 35.9, 34.3, 33.5. 32.6, 30.9, 30.3, 28.3, 26.2,24.6, 11.2.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxy-D-Homo-18-norandrostan-17-one (37)

Compound 36 (500 mg, 1.50 mmol) dissolved in MeOH (20 mL) was stirredwith 6 N HCl (6 mL) at room temperature for 24 h. The HCl wasneutralized by careful addition of aqueous NaHCO₃ solution and the MeOHremoved. Water was added and the product was extracted into EtOAc. Thecombined extracts were washed with brine, dried and the solvents removedto give the crude product as an off-white solid which was purified byflash column chromatography (silica gel, eluted with 40-50% EtOAc inhexanes). Compound 37 was obtained as a white solid (400 mg, 92%): mp227-229° C.; IR ν_(max) 3395, 2939, 2922, 2850, 1699, 1594, 1419, 1360,1320, 1264, 1208 cm⁻¹; ¹H NMR (CDCl₃) δ 4.04 (s, 1H), 0.71 (s, 3H); ¹³CNMR (CDCl₃) δ 211.9, 66.2, 52.9, 48.6, 47.4, 43.2, 41.2, 40.8, 38.4,36.1, 35.7, 34.3, 32.0, 31.0, 30.3, 28.9, 28.2, 24.6, 11.0.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxy-D-Homo-18-norandrostan-17-oneAcetate (38)

Compound 37 (370 mg, 1.27 mmol), AcOAc (0.5 mL) and Et₃N (1 mL) inCH₂Cl₂ (8 mL) were stirred at room temperature for 24 h. Aqueous sat.NaHCO₃ (5 mL) was carefully added and the mixture was stirred for 1 h.The product was extracted into CH₂Cl₂ and the combined extracts werewashed with brine, dried and the solvent removed to give an off-whitesolid. The crude product was purified by flash column chromatography(silica gel, eluted with 20-30% EtOAc in hexanes) to give product 38 asa white solid (400 mg, 95%): mp 141-143° C.; IR ν_(max) 2920, 2860,2733, 1717, 1446, 1361, 1246 cm⁻¹; ¹H NMR (CDCl₃) δ 4.96 (s, 1H), 2.00(s, 3H), 0.69 (s, 3H); ¹³C NMR (CDCl₃) δ 211.6, 170.4, 69.8, 69.6, 52.7,48.5, 47.3, 43.1, 41.1, 40.7, 39.2, 35.7, 34.2, 32.6, 32.5, 30.8, 30.2,27.9, 25.9, 24.5, 21.4, 21.3, 11.1, 11.0.

(3β,5α)-3-(Acetyloxy)-16,17-seco-D-homo-18-norandrostane-16,17-dioicAcid (39) and(3β,5α)-3-(Hydroxy)-16,17-seco-D-homo-18-norandrostane-16,17-dioic AcidDimethyl Ester (40)

A mixture of compound 38 (96 mg) and a CrO₃ solution (0.7 mL) [preparedby mixing CrO₃ (500 mg), water (0.7 mL) and acetic acid (0.8 mL)] and asolution of aqueous methanolic acetic acid (1 mL) [prepared by mixingacetic acid (30 mL), water (1 mL) and methanol (0.05 mL)] was stirred at60° C. for 4.5 h. The reaction was cooled to room temperature, water(2.5 mL) was added and the reaction was stirred at room temperature for13 h. Additional water (15 mL) was added and the product was extractedinto CH₂Cl₂. The combined extracts were dried and the solvent removed togive dicarboxylic acid 39 as a white solid which was immediatelyconverted without characterization to diester 40 upon stirring with dryHCl in MeOH (10 mL) [prepared by adding AcCl (3 mL) to MeOH (8 mL)] atroom temperature for 15 h. The HCl was cautiously neutralized withaqueous NaHCO₃ and the MeOH was removed. Water was added and the productwas extracted into EtOAc. The combined extracts were washed with brine,dried and solvent removed to give an oil. Purification by flash columnchromatography (silica gel, eluted with 40% EtOAc in hexanes) yieldedcompound 40 as a colorless oil (54 mg, 51%): IR ν_(max) 3445.55, 2924,2858, 1738, 1436, 1361, 1258 cm⁻¹; ¹H NMR (CDCl₃) δ 4.03 (s, 1H), 3.65(s, 6H), 0.71 (s, 3H); ¹³C NMR (CDCl₃) δ 173.7 (2×C), 66.3, 53.0, 51.5,51.4, 45.0, 40.8, 39.3, 38.8, 38.3, 36.1, 35.7, 35.3, 32.7, 31.9, 31.3,28.9, 28.4, 24.4, 11.0.

(3β,5β,8α,9β,10α,13α,14β,17a)-3-Hydroxy-16-oxo-18-norandrostane-17-carboxylicAcid Methy Ester (41)

A mixture of compound 40 (53 mg, 0.14 mmol), NaOMe (27 mg, 0.5 mmol) andTHF (8 mL) was heated at reflux for 0.5 h. The reaction was cooled,acidified with 1 N HCl to pH 3 and the product extracted into CH₂Cl₂(3×75 mL). The combined extracts were washed with brine, dried andsolvents removed to give a white solid. The crude product was purifiedby flash column chromatography (silica gel, eluted with 40% EtOAc inhexanes) gave pure product 41 as a white solid (34 mg, 71%): mp 136-138°C.; IR ν_(max) 3435, 2920, 2855, 1756, 1727, 1435, 1410, 1384, 1339,1261 cm⁻¹; ¹H NMR (CDCl₃) δ 4.06 (t, 1H, J=2.5 Hz), 3.75 (s, 3H), 2.86(d, 1H, J=2.5 Hz), 2.50 (dd, 1H, J=18.0 Hz, 5.8 Hz), 0.78 (s, 3H); ¹³CNMR (CDCl₃) δ 210.2, 169.5, 66.3, 61.9, 53.1, 52.3, 47.1, 46.6, 43.2,41.6, 38.7, 36.2, 35.7, 32.2, 31.9, 30.0, 28.9, 28.0, 24.5, 11.0.

(3β,5β,8α,9β,10α,13α,14β)-18-Norandrostan-16-one (42, KK-114)

A mixture of β-ketoester 41 (25 mg, 0.075 mmol), LiCl (100 mg) and DMFwas heated at 160° C. for 30 min under N₂. The reaction mixture wascooled, diluted with water and extracted with EtOAc. The combinedorganic extracts were dried and concentrated to give an off-white solid.The crude product was purified by flash column chromatography (silicagel, eluted with 30-40% EtOAc in hexanes) to give product 42 as a whitesolid (18 mg, 86%): mp 174-177° C.; [α]_(D) ²³ +171.9 (c 0.1, CHCl₃); IRν_(max) 3475, 2923, 2853, 1723 cm⁻¹; ¹H NMR (CDCl₃) δ 4.06 (br s, 1H),2.36 (m, 2H), 0.78 (s, 3H); ¹³C NMR (CDCl₃) δ 218.5, 66.4, 53.3, 50.2,45.9, 43.8, 43.3, 41.7, 38.8, 36.2, 35.8, 32.2, 32.0, 31.1, 29.0, 28.1,24.8, 11.1. Anal. (C₁₈H₂₈O₂): C, 78.21%; H, 10.21%. Found: C, 78.16%; H,10.12%.

In accordance with Scheme 4, the following compounds were prepared,using methods generally known in the art and as outlined below.

(5α)-Estrane-3,17-dione (43).

The known compound was prepared as described previously. (Stastna, E.;Rath, N. P.; Covey, D. F. The use of symmetry in enantioselectivesynthesis: Four pairs of chrysene enantiomers prepared from19-nortestosterone. Org. Biomol. Chem. 2011, 9, 4685-4694.)

(5α)-17-Oxo-3,4-secoestrane-2,3-dicarboxylic Acid (44) and(5α)-17-Oxo-3,4-secoestrane-2,3-dicarboxylic Acid Dimethyl Ester (45)

A solution of CrO₃ (10.9 g), H₂SO₄ (98%, 16 mL), and water (76 mL) wasadded dropwise to a stirred solution of compound 43 (7.9 g, 28.5 mmol)in AcOH (80 mL) at 65° C. The reaction was heated at 70° C. for 1 h.Then, crushed ice and water (500 mL) were added and the mixture wasstirred at room temperature for 1 h. Steroid 44 precipitated and wasfiltered, washed with water, and dried overnight at room temperature togive pure dicarboxylic acid (5.53 g, 60%) as a white solid. The aqueousphase was extracted with CH₂Cl₂ (2×150 mL), and the combined extractswere washed with brine (2×100 mL), dried and evaporated to afford impuredicarboxylic acid 44 (2 g, 21%) as an oily residue. Pure steroid 44 had:¹H NMR (300 MHz, CDCl₃) δ 0.88 (3H, s); ¹³C NMR (75 MHz, CDCl₃) δ 221.5,179.43, 179.25, 50.6, 47.9, 47.7, 43.2, 40.6, 39.4, 38.8, 36.0, 35.3,32.3, 31.6, 29.4, 26.0, 21.7, 13.9.

AcCl (6 mL, 23 mmol) was added to steroid 44 (7.53 g) dissolved in MeOH(100 mL) and the reaction was stirred at room temperature for 2 h. Then,water (50 mL) was added and the product was extracted into CH₂Cl₂ (2×100mL). The combined extracts were washed with water, dried and the solventremoved to yield an oily residue which was purified by flash columnchromatography (silica gel eluted with 15% EtOAc in hexanes) to givesteroid 45 (4.43 g, 52%) as an oil. Unreacted steroid 44 was reclaimedby washing the silica gel with MeOH and the esterification procedure wasrepeated to give additional product 45 (780 mg, 9%) as an oil: IRν_(max) 2925, 2858, 1737 cm⁻¹; ¹H NMR (CDCl₃) δ 3.65 (6H, s), 0.86 (3H,s); ¹³C NMR (CDCl₃) δ 220.9, 173.6 (2×C), 51.7, 51.6, 50.6, 47.99,47.90, 43.3, 40.6, 39.3, 39.1, 36.0, 35.3, 32.3, 31.7, 29.4, 25.9, 21.7,13.9.

(5α,17β)-17-Hydroxy-3,4-secoestrane-2,3-dicarboxylic Acid Dimethyl Ester(46)

Steroid 45 (1.55 g, 31.4 mmol) was dissolved in stirred EtOH (20 mL) andcooled in an ice-bath. NaBH₄ (218 g, 5.8 mmol) was added in smallportions. After 1.5 h, a solution of water (50 mL) and AcOH (2 mL) wasadded and the solution was stirred for 1 h. The product was extractedinto CH₂Cl₂ (2×125 mL), washed with an aqueous 1 N HCl, sat. aqueousNaHCO₃, brine, dried and the solvent removed. Flash columnchromatography (silica gel, eluted with 15% EtOAc in hexanes) gavesecosteroid 46 (1.16 g, 74%) as an oily product: IR ν_(max) 3452, 2950,2921, 2867, 1733 cm⁻¹; ¹H NMR (CDCl₃) δ 3.60-3.65 (7H, m), 0.73 (3H, s);¹³C NMR (CDCl₃) δ 173.7 (2×C), 82.0, 51.68, 51.62, 50.2, 47.9, 43.5,43.1, 41.2, 39.5, 39.2, 36.9, 35.4, 32.5, 30.7, 30.1, 26.3, 23.3, 11.2.

(3α,5α,17β)-17-Hydroxy-2-oxo-A-norestrane-3-carboxylic Acid Methyl Ester(47)

A NaOMe solution (5 mL) was prepared by dissolving Na (1.14 g, 49 mmol)in MeOH (25 mL) followed by MeOH evaporation on a rotary evaporator. DryTHF (30 mL) was added and the flask was filled with N₂. Steroid 46 (5 g,14.1 mmol) dissolved in dry THF (50 mL) was slowly added. The reactionmixture was heated at 100° C. for 1 h under N₂ and then allowed toattain room temperature. Then 1 N HCl (15 mL) was slowly added and theproduct was extracted into CH₂Cl₂ (2×100 mL). The combined extracts werewashed with brine, dried and the solvent removed. Flash columnchromatography (silica gel, eluted with 15% EtOAc in hexanes) gaveproduct 47 (3.7 g, 81%) as a white solid: mp 138-142° C.(EtOAc/hexanes); IR ν_(max) 3440, 2918, 2866, 1756, 1727 cm⁻¹; ¹H NMR(CDCl₃) δ 3.75 (3H, s), 3.67 (t, 1H, J=8 Hz), 2.88 (d, 1H, J=12.6 Hz),2.48 (dd, 1H, J=6.6 Hz, 18 Hz), 0.77 (3H, s). ¹³C NMR (CDCl₃) δ210.1,169.7, 81.9, 62.1, 52.4, 49.7, 48.7, 47.5, 45.7, 43.6, 43.3, 41.6, 36.5,30.5, 30.2, 29.9, 27.1, 23.3, 11.4. Anal. (C₁₉H₂₈O₄): C, 71.22%; H,8.81%. Found: C, 71.12%; H, 8.68%.

(5α,17β)-17-Hydroxy-A-norestran-2-one (48)

LiCl (1.95 g, 46.1 mmol) was added to a solution of steroid 47 (3.7 g,11.5 mmol) dissolved in DMF (50 mL) and water (0.5 mL) and the reactionwas heated at 160° C. for 35 min. Then, crushed ice and water were addedand the product was extracted into CH₂Cl₂ (2×120 mL). The combinedextracts were washed with water and dried. After solvent evaporation,the residue was purified by flash column chromatography (silica gel,eluted with 10% EtOAc in hexanes) to give product 48 (2.6 g, 85%) as awhite solid: mp 177-179° C. (EtOAc/hexanes); IR ν_(max) 3450, 2915,2861, 1732 cm⁻¹; ¹H NMR (CDCl₃) δ 0.77 (3H, s), 2.41-2.31 (2H, m), 3.66(t, 1H, J=8 Hz). ¹³C NMR (CDCl₃) δ 218.3, 82.0, 49.9, 48.9, 48.6, 46.1,44.2, 43.9, 43.6, 41.7, 36.6, 30.9, 30.64, 30.61, 27.1, 23.4, 11.4.Anal. (C₁₇H₂₆O₂): C, 77.82%; H, 9.99%. Found: C, 77.69%; H, 10.02%.

(5α,17β)-17-[[(4-Methylphenyl)sulfonyl]oxy]-A-norestran-2-one (49)

A solution of steroid 39 (2.46 g, 9.37 mmol), DMAP (57 mg, 0.49 mmol),and p-TsCl (6.25 g, 32.8 mmol) in anhydrous pyridine (50 mL) was heatedat 65° C. overnight. The reaction mixture was poured into ice-water andthe product extracted into CH₂Cl₂ (2×75 mL). The combined extracts werewashed with aqueous HCl, aqueous NaHCO₃, brine, and dried. After solventevaporation, the oily residue was purified by flash columnchromatography (silica gel, eluted with 10% EtOAc in hexanes) to givesteroid 39 (3.56 g, 91%) as a white solid: mp 138-139° C.(ether/hexanes); IR ν_(max) 2920, 2858, 1741, 1598, 1357, 1188, 1176cm⁻¹; ¹H NMR (CDCl₃) δ 7.80-7.77 (2H, m), 7.34-7.31 (2H, m), 4.28 (t,1H, J=8 Hz), 2.45 (3H, s), 2.33 (dd, 2H, J=6.6 Hz, 18 Hz), 0.82 (3H, s).¹³C NMR (CDCl₃) 5217.9, 144.6, 134.6, 129.8 (2×C), 128.0 (2×C), 90.0,48.9, 48.6, 48.4, 45.9, 44.1, 43.8, 43.6, 41.2, 36.0, 30.8, 30.4, 27.7,26.8, 23.3, 21.8, 12.0. Anal. (C₂₄H₃₂O₄S): C, 69.20%; H, 7.74%. Found:C, 69.09%; H, 7.35%.

(5α,17β)-2-Methylene-17-[[4-(methylphenyl)sulfonyl]oxy]-A-norestrane(50)

A solution of n-BuLi (2.5 M, 24.1 mmol, 9.6 mL) was added dropwise to asolution of MeP(Ph)₃Br (8.85 g, 24.7 mmol) in dry benzene (70 mL) anddry THF (12 mL) under N₂ and the mixture was stirred for 30 min. Asolution of steroid 49 (2.58 g, 6.19 mmol) in dry benzene (35 mL) wasadded and stirred at room temperature. After 6 h, the reaction wasdiluted with water (50 mL) and extracted with EtOAc (2×75 mL). Thecombined extracts were washed with brine, dried and the solventsevaporated. Flash column chromatography on (silica gel, eluted with 5%EtOAc in hexanes) gave steroid 50 (2.05 g, 80%) as a white solid: mp136-137° C. (EtOAc/hexanes); IR ν_(max) 2920, 2855, 1657, 1598, 1359cm⁻¹; ¹H NMR (CDCl₃) δ 7.80-7.77 (2H, m), 7.34-7.31 (2H, m), 4.83 (2H,m), 4.27 (t, 1H, J=8 Hz), 2.45-2.36 (5H, m), 0.81 (3H, s); ¹³C NMR(CDCl₃) δ 151.5, 144.5, 134.6, 129.8 (2×C), 128.0 (2×C), 105.9, 90.3,51.0, 49.0, 48.9, 46.7, 43.7, 41.3, 39.6, 37.6, 36.2, 31.0, 30.8, 27.8,26.7, 23.5, 21.8, 12.1. Anal. (C₂₅H₃₁O₃S): C, 72.42%; H, 8.27%. Found:C, 72.59%; H, 8.07%.

(5α)-17-Methyl-2-Methylene-A-norgon-13(17)-ene (51)

Steroid 50 (2 g, 4.8 mmol) was dissolved in anhydrous toluene (50 mL)and heated to 100° C. MeMgBr (3.0 M in Et₂O, 8 mL, 24 mmol) was addeddropwise to the stirring hot solution under an N₂ atmosphere and a whiteprecipitate appeared. The reaction was heated for 1 h at 115° C. Theflask was cooled, a few pieces of crushed ice were added, and the pH ofthe solution was adjusted to pH 2 by dropwise addition of 2 N aqueousH₂SO₄. The toluene layer was separated and the aqueous layer wasextracted with EtOAc (2×100 mL). The combined extracts were washed withbrine, dried and the solvents evaporated. Flash column chromatography on(silica gel, eluted with 1% EtOAc in hexanes) gave steroid 51 (1.04 g,90%) as an oily product: IR ν_(max) 3067, 2921, 2851, 1657, 1441 cm⁻¹;¹H NMR (CDCl₃) δ 4.86 (2H, m), 1.62 (3H, s). ¹³C NMR (CDCl₃) δ 151.9,136.7, 128.3, 105.7, 100.2, 52.6, 51.5, 51.3, 47.1, 46.4, 39.7, 37.8,37.4, 31.5, 31.2, 28.4, 25.6, 13.6.

(3aS,5aR,6S,9aR,9bS)-Decahydro-6-(3-oxobutyl)-1H-benz[e]indene-2,7-dione(52)

A solution of steroid 51 (760 mg, 3.13 mmol) in CH₂Cl₂ (55 mL) wastreated with O₃ at −78° C. until a blue color persisted (ca. 1 hr). O₂was passed through the solution for 30 min until the blue colordisappeared. AcOH (50 mL) was added and the CH₂Cl₂ was evaporated undervacuum without heating. Then, AcOH (10 mL) and Zn dust (2.03 g, 31 mmol)were added and the reaction mixture was stirred at room temperature for1.5 h. Zn dust was filtered off through cotton, washing with CH₂Cl₂ (100mL). The Zn dust was stirred with EtOAc (50 mL) for 1 h. The solids werefiltered off, the combined solvents were evaporated and the product waspurified by flash column chromatography (silica gel, eluted with 20%EtOAc in hexanes) to give compound 52 (390 mg, 51%) as an oil: IRν_(max) 3406, 2919, 2859, 1742, 1709 cm⁻¹; ¹H NMR (CDCl₃) 52.09 (3H, s);¹³C NMR (CDCl₃) δ 217.0, 211.6, 209.1, 53.9, 48.4, 47.4, 46.5, 45.6,43.6, 43.2, 41.6, 40.9, 32.0, 31.1, 30.5, 30.0, 19.5.

(8α,9β,10α,13α,14β)-Gon-4-ene-3,16-dione (53)

A solution of NaOH [10% w/v in MeOH/water (9:1), 2 mL] was added to asolution of compound 52 (392 g, 1.41 mmol) in MeOH (20 mL) and themixture was stirred at room temperature. After 3 h, a few pieces ofcrushed ice were added, the pH was adjusted to pH 2 by adding aqueous 1N HCl, and the product was extracted into CH₂Cl₂ (2×70 mL). The combinedextracts were washed with brine, dried and the solvent evaporated.Purification by flash column chromatography (silica gel, eluted with 20%EtOAc in hexanes) gave compound 53 (302 mg, 82%) as a white solid: mp147-148° C. (EtOAc/hexanes); IR ν_(max) 2932, 2854, 1740, 1662, 1612cm⁻¹; ¹H NMR (CDCl₃) δ 5.84 (1H, s); ¹³C NMR (CDCl₃) δ 217.4, 199.8,165.8, 124.9, 48.7, 48.6, 46.5, 45.8, 43.6, 43.2, 42.6, 36.6, 35.3,31.4, 30.7, 30.3, 26.5. Anal. (CO₁₇H₂₂O₂) C, 79.03%; H, 8.58%. Found: C,79.09%; H, 8.38%.

(5β,8α,9β,10α,13α,14β)-Gonane-3,16-dione (54)

Anhydrous NH₃ (10 mL) was condensed using a Dewar condenser into athree-neck flask containing Li metal (20 mg, 2.9 mmol) at −78° C. Then,anhydrous THF (12 mL) was added and the resulting blue solution wasstirred for 0.5 h. A solution of compound 53 (150 mg, 0.58 mmol) in dryTHF (6 mL) was added dropwise to the vigorously stirred solution. After2 h of stirring, the reaction color was discharged by careful additionof solid NH₄Cl in portions and left overnight while the NH₃ evaporated.The reaction was then acidified with aqueous 1 N HCl and the product wasextracted into EtOAc (2×50 mL). The combined organic phases were washedwith brine, dried and the solvent evaporated. The residue was dissolvedin acetone (50 mL) and Jones reagent was added dropwise until an orangecolor persisted. The course of the reaction was checked by TLC. Then,2-propanol was added dropwise until the reaction mixture turned green.After 30 min, the reaction mixture was poured into water-ice. Theproduct was extracted into CH₂Cl₂ (2×30 mL). The combined extracts werewashed with brine, dried and the solvent was evaporated. Flash columnchromatography (silica gel, eluted with 15% EtOAc in hexanes) gavecompound 54 (95 mg, 63%) as a white solid: mp 188-189° C.(EtOAc/hexanes); IR ν_(max) 2914, 2867, 1740, 1705 cm⁻¹; ¹H NMR (CDCl₃)δ 0.90-2.42 (24H, m); ¹³C NMR (CDCl₃) δ 218.1, 211.6, 49.1, 48.7, 47.3,46.8, 46.0, 45.9, 43.7, 43.5, 43.4, 41.4, 33.8, 31.1, 31.0, 30.4, 30.0.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxygonan-16-one (55, ES-32)

K-Selectride (1M in THF, 0.45 mL) was added dropwise under N₂ to acooled solution (−78° C.) of compound 54 (108 mg, 0.41 mmol) inanhydrous THF (15 mL). After 2 h stirring at −78° C., water (2 mL) wasadded and the mixture was allowed to reach room temperature. Then,aqueous NaOH (2 mL, 6 M), and 30% H₂O₂ (2 mL) were added and thereaction was stirred for 30 min. The product was extracted with CH₂Cl₂(2×50 mL), the combined extracts were washed with aqueous HCl (1 N),saturated aqueous NaHCO₃, and brine. Solvent was dried and evaporated.Flash column chromatography (silica gel, eluted with 10% EtOAc inhexanes) gave product 55 (76 mg, 70%) as a white solid: mp 168-169° C.(EtOAc/hexanes); [α]_(D) ²³ +218.6 (c 0.17, CHCl₃). IR ν_(max) 3466,2917, 2846, 1724 cm⁻¹; ¹H NMR (CDCl₃) δ 4.08 (1H, m), 2.30-2.41 (2H, m),1.97-2.10 (2H, m). ¹³C NMR (CDCl₃) δ 218.5, 66.5, 49.3, 47.7, 47.3,47.2, 46.1, 43.8, 43.6, 40.7, 35.9, 33.5, 33.1, 31.4, 31.1, 29.6, 23.6.Anal. (C₁₇H₂₆O₂): C, 77.82%; H, 9.99%. Found: C, 78.02%; H, 9.79%.

In accordance with Scheme 5, the following compounds were prepared,using methods generally known in the art and as outlined below.

(8α,9β,10α,13α,14β)-Androst-5-ene-3,17-dione, Cyclic3,17-bis(1,2-ethanediyl Acetal) (56)

To a solution of the compound 1 (600 mg, 2.08 mmol) in benzene (150 mL)was added ethylene glycol (1.0 mL) and PTSA (150 mg) at 23° C. Themixture was refluxed in a Dean-Stark apparatus for 16 h. Solvent wasremoved and the residue was purified by flash column chromatography(silica gel, eluted with 17% EtOAc in hexanes) to give compound 56 (605mg, 78%) as an oil: ¹H NMR (CDCl₃) δ 5.32-5.30 (m, 1H), 3.96-3.81 (m,8H), 2.56-2.52 (m, 1H), 1.00 (s, 3H), 0.83 (s, 3H); ¹³C NMR (CDCl₃) δ140.0, 121.8, 119.4, 109.3, 65.1, 64.5, 64.4, 64.1, 50.4, 49.4, 45.7,41.7, 36.6, 36.2, 34.1, 32.1, 31.0, 30.9, 30.5, 22.7, 20.4, 18.8, 14.1.

(5α,6α,8α,9β,10α,13α,14β)-6-Hydroxyandrostane-3,17-dione, Cyclic3,17-bis(1,2-ethanediyl Acetal) (57) and(5β,6β,8α,9β,10α,13α,14β)-6-Hydroxyandrostane-3,17-dione, Cyclic3,17-bis(1,2-ethanediyl Acetal) (58)

To a solution of compound 56 (600 mg, 1.61 mmol) in THF (30 mL) wasadded BH₃.THF complex (3.0 mL, 1.0 M, 3.0 mmol) at 0° C. After 1 h, themixture was warmed up to 23° C. for an additional 1 h. To the reactionwas slowly added 3 M NaOH (20 mL) and H₂O₂ (5 mL) at 23° C. The reactionwas stirred for 1 h and the product extracted into EtOAc (3×100 mL). Thecombined extracts were washed with brine (3×50 mL). Solvent was removedand the residue was purified by flash column chromatography (silica gel,eluted with 33% EtOAc in hexanes) to give products 57 and 58 as oils.

Product 57 (290 mg, 46%) had: ¹H NMR (CDCl₃) δ 3.91-3.78 (m, 8H), 3.66(d, J=2.0 Hz, 1H), 1.09 (s, 3H), 0.81 (s, 3H); ¹³C NMR (CDCl₃) δ 119.3,109.2, 72.4, 65.1, 64.4, 64.1, 64.0, 50.2, 47.6, 45.9, 39.9, 35.6, 34.6,34.3, 34.1, 33.4, 30.8, 30.6, 29.6, 25.2, 22.5, 20.1, 14.4.

Product 58 (50 mg, 8%) had: ¹H NMR (CDCl₃) δ 3.91-3.79 (m, 8H),3.58-3.30 (m, 1H), 0.80 (s, 3H), 0.79 (s, 3H); ¹³C NMR (CDCl₃) δ 119.2,109.0, 69.4, 65.0, 64.5, 64.1, 64.0, 53.1, 50.6, 49.9, 45.9, 41.0, 36.3,36.2, 34.5, 34.1, 32.1, 30.9, 30.4, 22.6, 20.4, 14.3, 12.5.

(5β,8α,9β,10α,13α,14β)-Androstane-3,6,17-trione, Cyclic3,17-bis(1,2-ethanediyl Acetal) (59)

To a solution of unseparated products 57 and 58 (340 mg, 0.87 mmol) inCH₂Cl₂ (20 ml) was added pyridium chlorochromate (PCC, 648 mg, 3.0 mmol)at 23° C. The reaction was stirred 2 h and then transferred to a shortsilica gel column to give crude product 59 (336 mg). Crude product 59was dissolved in methanol (30 mL) and then added K₂CO₃ (2.0 g) was addedat 23° C. The reaction was refluxed for 16 h. methanol was removed andthe residue was purified by flash column chromatography (silica gel,eluted with 20% EtOAc in hexanes) to give product 59 (200 mg, 59%) as anoil: ¹H NMR (CDCl₃) δ 3.91-3.79 (m, 8H), 2.47 (t, J=7.8 Hz, 1H), 2.28(dd, J=12.9 Hz, 2.3, 1H), 0.78 (s, 3H), 0.70 (s, 3H); ¹³C NMR (CDCl₃) δ211.0, 118.8, 108.8, 65.1, 64.4, 64.1, 64.0, 55.8, 53.2, 50.4, 46.1,45.8, 40.7, 37.9, 35.5, 33.9, 30.6, 30.1, 29.7, 22.3, 20.7, 14.2, 12.3.

(5β,8α,9β,10α,13α,14β)-6-Methylene-androstane-3,17-dione, Cyclic3,17-bis(1,2-ethanediyl Acetal) (60)

In a dry flask, methylphenylphosphonium bromide (2.1 g, 6.0 mmol) andTHF (30 mL) were combined. Potassium t-butoxide (560 mg, 5.0 mmol) wasadded. The mixture was stirred under N₂ for 45 min at reflux. Compound59 (200 mg, 0.51 mmol) was dissolved in THF (10 mL) and transferred bysyringe to the refluxing reaction. The yellow mixture was stirred for anadditional 1 h. at reflux. After cooling, brine (50 mL) was added andthe product extracted into EtOAc (2×100 mL). Solvent was removed and theresidue was purified by flash column chromatograph (silica gel, elutedwith 14% EtOAc in hexanes) to give product 60 (176 mg, 88%) as oil: ¹HNMR (CDCl₃) δ 4.65 (s, 1H), 4.35 (s, 1H), 3.91-3.78 (m, 8H), 2.25 (d,J=12.5 Hz, 1H), 0.78 (d, J=1.6 Hz, 3H), 0.65 (d, J=1.2 Hz, 3H); ¹³C NMR(CDCl₃) δ 149.3, 119.2, 109.5, 105.5, 65.1, 64.4, 64.1, 64.0, 53.9,50.1, 48.1, 45.9, 41.1, 37.6, 37.5, 35.4, 34.1, 33.4, 30.8, 30.5, 22.5,20.8, 14.3, 11.5.

(5β,8α,9β,10α,13α,14β)-6-Methylene-androstane-3,17-dione (61)

To a solution of compound 60 (176 mg, 0.45 mmol) in acetone/H₂O (20 mL/1mL) was added PTSA (50 mg) at 23° C. The reaction was stirred for 6 hand then NaHCO₃ (solid, 0.5 g) was added. Solvent was removed and theresidue was purified by flash column chromatograph (silica gel, elutedwith 20% EtOAc in hexanes) to give product 61 (129 mg, 95%) as an oil:¹H NMR (CDCl₃) δ 4.81 (s, 1H), 4.43 (s, 1H), 0.88 (s, 3H), 0.84 (s, 3H);¹³C NMR (CDCl₃) δ 220.4, 211.8, 147.1, 107.2, 54.0, 51.0, 50.7, 47.7,40.4, 40.3, 37.9, 37.8, 37.6, 36.6, 35.7, 31.2, 21.6, 20.8, 13.7, 11.6.

In accordance with Scheme 6, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxy-6-methylene-androstan-17-one (62)

To a solution of compound 61 (128 mg, 0.43 mmol) in THF (20 mL) wasslowly added K-selectride (1.0 mL, 1.0 M, 1.0 mmol) at −78° C. After 2h, 3 M NaOH (20 mL) and H₂O₂ (5 mL) were added at −78° C. The reactionwas then warmed up to 23° C. for 1 h. The product was extracted intoEtOAc (3×100 mL) and the combined extracts washed with brine (3×50 mL).Solvent was removed and the residue was purified by flash columnchromatograph (silica gel, eluted with 20% EtOAc in hexanes) to giveproduct 62 (105 mg, 82%): ¹H NMR (CDCl₃) δ 4.72 (d, J=1.6 Hz, 1H), 4.43(d, J=1.6 Hz, 1H), 4.15-4.13 (m, 1H), 0.83 (s, 3H), 0.66 (s, 3H); ¹³CNMR (CDCl₃) δ 221.2, 149.4, 106.0, 66.0, 54.6, 51.4, 47.9, 43.5, 40.9,38.3, 36.9, 35.8, 31.6, 31.4, 31.2, 28.5, 21.7, 20.3, 13.8, 11.4.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxy-6-Methylene-16-(phenylmethylene)-androstan-17-one(63)

Compound 62 (105 mg, 0.35 mmol) and benzaldehyde (0.14 mL, 1.4 mmol)were added to KOH (50 mg) dissolved in EtOH (10 mL) and the reaction wasstirred at room temperature for 16 h. Ethanol was removed and theresidue was purified by flash column chromatography (silica gel, elutedwith 20% EtOAc in hexanes) to give product 63 (121 mg, 86%): ¹H NMR(CDCl₃) δ 7.56-7.26 (m, 6H), 4.79 (s, 1H), 4.47 (s, 1H), 4.17-4.4.14 (m,1H), 2.91 (dd, J=15.7 Hz, 6.3 Hz, 1H), 0.95 (d, J=1.9 Hz, 3H), 0.72 (d,J=2.3 Hz, 3H); ¹³C NMR (CDCl₃) δ 209.7, 149.3, 135.9, 135.5, 133.1,130.3 (2×C), 129.2, 128.6 (2×C), 106.1, 66.0, 54.7, 49.5, 47.6, 43.5,41.0, 38.4, 36.6, 31.5, 31.2, 29.1, 28.4, 20.3, 14.5, 11.5.

(3β,5β,8α,9β,10α,13α,14β,17α)-6-Methylene-16-(phenylmethylene)-androstane-3,17-diol(64)

Compound 63 was dissolved in EtOH, cooled to 0° C. and CeCl₃.7 H₂O (745mg, 2.0 mmol) and NaBH₄ (766 mg, 2.0 mmol) were added. The reaction wasallowed to warm to room temperature and stirring was continued for 3 h.Glacial AcOH ((7 mL) was added and the product extracted into EtOAc(3×50 mL). The combined extracts were dried and the solvents removed togive product 64 (121 mg, 99%) as an oil: ¹H NMR (CDCl₃) δ 7.32-7.24 (m,5H), 7.14-7.10 (m, 1H), 6.44 (d, J=2.3 Hz, 1H), 4.69 (s, 1H), 4.37 (s,1H), 4.09-4.08 (m, 1H), 3.98 (s, br, 1H), 0.62 (s, 3H), 0.60 (s, 3H);¹³C NMR (CDCl₃) δ 149.6, 146.0, 137.8, 128.3 (2×C), 128.2 (2×C), 126.4,123.0, 105.8, 84.9, 66.1, 54.8, 48.5, 43.5, 43.1, 41.7, 38.4, 36.9,36.3, 31.6, 31.3, 30.8, 29.2, 28.4, 20.7, 11.5, 11.2.

(3β,5β,8α,9β,10α,13α,14β,17α)-6-Methylene-16-(phenylmethylene)-androstane-3,17-diolDiacetate (65)

Compound 64 was dissolved in CH₂Cl₂ (10 mL) and AcOAc (0.14 mL, 1.5mmol), NEt₃ (0.42 ml, 3.0 mmol) and DMAP (20 mg) were added the reactionwas stirred at room temperature for 1 h. Aqueous saturated NaHCO₃ wasthen added. After 1 h, the product was extracted into CH₂Cl₂ (3×50 mL).The combined extracts were dried and solvents removed to give an oil.The crude product was purified by flash column chromatography (silicagel, eluted with 25-35% EtOAc in hexanes) to give pure product 65 (147mg, 100%): ¹H NMR (CDCl₃) δ 7.36-7.18 (m, 5H), 6.22 (s, 1H), 5.37 9s,1H), 5.12 (s, 1H), 4.77 (s, 1H), 4.43 (s, 1H), 2.70 (dd, J=16.8 Hz, 7.0Hz, 1H), 2.19 (d, J=1.2 Hz, 3H), 2.05 (d, J=1.2 Hz, 3H), 0.76 (s, 3H),0.69 (s, 3H); ¹³C NMR (CDCl₃) δ 171.1, 170.6, 148.9, 140.6, 137.4, 128.2(2C), 128.1 (2C), 126.5, 123.7, 106.1, 84.4, 69.5, 54.3, 48.8, 44.4,43.0, 41.4, 38.0, 36.6, 36.3, 32.2, 30.7, 28.3, 25.6, 21.4, 21.1, 20.5,12.2, 11.5.

(3β,5β,8α,9β,10α,13α,14β,17α)-3,17-Dihydroxyandrostane-6,16-dioneDiacetate (66)

A stream of O₃ was bubbled through a solution of compound 65 (147 mg,0.36 mmol) dissolved in MeOH/EtOAc (2:1; 20 mL) at −78° C. until a bluecolor persisted for 10 min. The excess O₃ was purged from the reactionusing an O₂ stream as evidenced by the solution becoming colorless. Me₂Swas then added (2 mL) and the reaction was allowed to warm to roomtemperature and then allowed to stir for 14 h. Solvents were removed andthe residue was purified by flash column chromatography (silica gel,eluted with 30-40% EtOAc in hexanes) to yield compound 65 as a foamywhite solid (106 mg, 85%): 5.10-5.09 (m, 1H), 4.85 (s, br, 1H), 2.14 (s,3H), 2.02 (s, 3H), 0.81 (s, 3H), 0.76 (s, 3H); ¹³C NMR (CDCl₃) δ 210.0,209.6, 170.3, 170.2, 85.2, 68.5, 53.4, 52.5, 46.0, 45.6, 41.9, 41.1,36.4, 35.8, 35.7, 32.0, 25.1, 24.9, 21.4, 20.6, 20.2, 12.4, 12.3.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostane-6,16-dione Acetate (67)

Freshly prepared Sm filings (1.5 mmol, 225 mg) were added to THF (5 mL)and I₂ (1.0 mmol, 254 mg) in THF (5 mL) at room temperature. Thesuspension was stirred under N₂. After 30 min, the mixture became deepblue indicating SmI₂ formation and stirring was continued for another 30min. Compound 66 (106 mg, 0.36 mmol) in THF/MeOH (10/0.2, 10.2 mL) wasadded. After 1 h, 10% aqueous Na₂CO₃ (20 mL) was added and the productwas extracted into EtOAc (3×50 mL). The combined extracts were washedwith brine (2×20 mL) and dried. The crude product was dissolved inacetone (20 mL) and cooled to 0° C. Jones reagent was added until abrownish orange color persisted for 5 min. After 10 min, 2-propanol (1mL) and then brine (30 mL) were added. The product was extracted intoEtOAc (3×50 mL). Solvents were removed and the residue was purified byflash column chromatography (silica gel, eluted with 30% EtOAc inhexanes) to give product 67 (73 mg, 81%): ¹H NMR (CDCl₃) δ 5.09 (d,J=2.0 Hz, 1H), 2.01 (d, J=2.4 Hz, 3H), 0.87 (s, 3H), 0.76 (s, 3H); ¹³CNMR (CDCl₃) δ 217.0, 210.5, 170.2, 68.6, 55.5, 53.6, 52.5, 51.8, 46.7,41.2, 39.3, 38.8, 37.6, 37.0, 32.0, 25.2, 24.9, 21.4, 20.6, 18.0, 12.4.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostane-6,16-dione (68, MQ-124)

To a solution of compound 66 (73 mg, 0.21 mmol) in MeOH (10 mL) wasadded K₂CO₃ (500 mg) at 23° C. The mixture was refluxed for 4 h, MeOHwas removed under reduced pressure and the residue was purified by flashcolumn chromatography (silica gel, eluted with 30% EtOAc in hexanes) togive product 68 (61 mg, 95%): mp 205-207° C.; [α]_(D) ²³ +173.1 (c 0.17,CHCl₃); IR ν_(max) 3445, 1741, 1701 cm⁻¹; ¹H NMR (CDCl₃) δ 4.15 (s, br,1H), 2.76-2.73 (m, 1H), 0.87 (s, 3H), 0.75 (d, J=3.9 Hz, 3H); ¹³C NMR(CDCl₃) δ 217.4, 211.6, 65.1, 55.4, 53.5, 51.7, 51.6, 46.7, 41.5, 39.3,38.8, 37.6, 37.0, 31.3, 28.0, 27.5, 20.6, 18.0, 12.3.

(3β,5β,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-androstane-6,16-dione (69)

Compound 68 (40 mg, 0.13 mmol) was dissolved CH₂Cl₂ (10 mL) and cooledto 0° C. (i-Pr)₂EtN (0.26 mL, 1.5 mmol) and ClCH₂OMe (0.15 ml, 2.0 mmol)were added and the reaction was stirred at room temperature for 6 h. Thereaction mixture was made basic by adding aqueous NaHCO₃ solution andthe product extracted into CH₂Cl₂. The combined extracts were washedwith brine, dried and solvent removed to give a viscous liquid. Thecrude product was purified by flash column chromatography (silica gel,eluted with 25% EtOAc in hexanes) to give product 69 as a colorlessliquid (41 mg, 89%): ¹H NMR (CDCl₃) δ 4.61 (q, J=3.9 Hz, 2H), 3.92 (s,br, 1H), 3.35 (t, J=6.0 Hz, 3H), 2.67 (dd, J=10.2 Hz, 2.4 Hz, 1H), 0.87(s, 3H), 0.76 (s, 3H); ¹³C NMR (CDCl₃) δ 217.1, 211.3, 94.4, 70.0, 55.4,55.2, 53.6, 52.3, 51.8, 46.7, 41.2, 39.3, 38.8, 37.6, 37.0, 31.9, 25.5,25.3, 20.6, 18.0, 12.5.

(3β,5β,6α,8α,9β,10α,13α,14β,16α)-3-(Methoxymethoxy)-androstane-6,16-diol(70)

Compound 69 (40 mg, 0.12 mmol) was dissolved in stirred EtOH (10 mL) andcooled in an ice-bath. NaBH₄ (38 mg, 1.0 mmol) was added in smallportions. After 1 h, a solution of water (20 mL) and AcOH (1 mL) wasadded and the solution was stirred for 1 h. The product was extractedinto CH₂Cl₂ (2×50 mL), washed with an aqueous 1 N HCl, sat. aqueousNaHCO₃, brine, dried and the solvent removed. Flash columnchromatography (silica gel, eluted with 70% EtOAc in hexanes) gaveproduct 70 (30 mg, 75%): ¹H NMR (CDCl₃) δ 4.67-4.63 (m, 2H), 4.41-4.37(m, 1H), 3.94 (s, br, 1H), 3.74 (s, br, 1H), 3.38-3.34 (m, 3H), 1.02 (s,3H), 0.97 (s, 3H); ¹³C NMR (CDCl₃) δ 94.6, 72.1, 71.9, 71.8, 55.2, 54.3,53.8, 51.3, 42.3, 40.2, 39.9, 38.9, 37.2, 36.0, 34.5, 30.9, 30.1, 26.3,20.2, 19.1, 15.1.

(3β,5β,6α,8α,9β,10α,13α,14β,16α)-6,16-Dimethoxy-3-(methoxymethoxy)-androstane(71)

To a solution compound 70 (30 mg, 0.09 mmol) in THF (15 mL) was addedNaH (80 mg, 60% in mineral oil, 2.0 mmol) at 23° C. The mixture wasrefluxed for 1 h. Iodomethane (0.5 mL) was added via syringe. Themixture was refluxed for addition 1 h. After cooling, water was slowlyadded and the product extracted into EtOAc (3×50 mL). The combinedextracts were washed with brine, dried and solvent removed to give aviscous liquid. The crude product was purified by flash columnchromatography (silica gel, eluted with 25% EtOAc in hexanes) to giveproduct 71 (22 mg, 69%): ¹H NMR (CDCl₃) δ 4.67-4.63 (m, 2H), 3.91 (s,br, 1H), 3.87-3.82 (m, 1H), 3.36 (s, 3H), 3.35 (s, 3H), 3.25 (s, 3H),3.13 (s, br, 1H), 0.94 (s, 3H), 0.90 (s, 3H); ¹³C NMR (CDCl₃) δ 94.5,81.3, 81.1, 72.0, 57.2, 56.7, 55.1, 54.5, 53.1, 47.3, 42.8, 39.9, 39.0,36.3, 34.4, 34.2, 31.2, 30.4, 29.7, 26.3, 20.3, 18.9, 14.7.

(3β,5β,6α,8α,9β,10α,13α,14β,16α)-6,16-Dimethoxyandrostan3-ol (72,MQ-125)

Compound 71 (22 mg, 0.06 mmol) dissolved in MeOH (10 mL) was stirredwith 6 N HCl (10 mL) at room temperature for 6 h. The HCl wasneutralized by careful addition of aqueous NaHCO₃ solution and the MeOHremoved. Water was added and the product was extracted into EtOAc. Thecombined extracts were washed with brine, dried and the solvents removedto give the crude product as an off-white solid which was purified byflash column chromatography (silica gel, eluted with 40-50% EtOAc inhexanes). Compound 72 was obtained as a white solid (8 mg, 42%): mp127-129° C.; [α]_(D) ²³ +44.0 (c 0.05, CHCl₃); IR ν_(max) 3401, 1452cm⁻¹; ¹H NMR (CDCl₃) δ 4.14 (s, br, 1H), 3.86-3.84 (m, 1H), 3.26 (d,J=1.6 Hz, 3H), 3.24 (d, J=1.5 Hz, 3H), 3.12 (s, br, 1H), 0.93 (s, 3H),0.90 (s, 3H); ¹³C NMR (CDCl₃) δ 81.3, 81.1, 66.8, 57.2, 56.7, 54.5,53.0, 47.3, 42.1, 39.9, 39.0, 36.5, 34.4, 33.7, 33.3, 30.4, 29.7, 29.1,20.3, 18.9, 14.5.

In accordance with Scheme 7, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3α,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-17-one, Cyclic17-(1,2-ethanediyl Acetal) (73)

To a solution of compound 5 (950 mg, 3.23 mmol) in benzene (150 mL) wasadded ethylene glycol (2.0 mL) and PTSA (200 mg) at 23° C. The mixturewas refluxed in a Dean-Stark apparatus for 16 h. Solvent was removedunder reduced pressure and the residue was purified by flash columnchromatography (silica gel, eluted with 20% EtOAc in hexanes) to giveproduct 73 (1.08 mg (100%) as a oil: ¹H NMR (CDCl₃) δ 3.92-3.83 (m, 4H),3.60-3.54 (m, 1H), 0.82 (s, 3H), 0.79 (s, 3H); ¹³C NMR (CDCl₃) δ 119.4,71.2, 65.1, 64.5, 54.1, 50.3, 45.9, 44.8, 38.1, 37.0, 35.7, 35.5, 34.1,31.4, 31.3, 30.7, 28.5, 22.6, 20.6, 14.4, 12.3.

(3α,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-17-one acetate, Cyclic17-(1,2-ethanediyl Acetal) (74)

Compound 73 (1.08 g, 3.23 mmol) was dissolved stirred in CH₂Cl₂ (30 mL)and AcOAc (0.7 mL, 7.5 mmol), NEt₃ (2.1 ml, 15 mmol) and DMAP (50 mg)were added. After 1 h, aqueous saturated NaHCO₃ was then added. After 1h, the product was extracted into CH₂Cl₂ (3×50 mL). The combinedextracts were dried and solvents removed to give an oil. The crudeproduct was purified by flash column chromatography (silica gel, elutedwith 20% EtOAc in hexanes) to give product 74 (1.22 g, 100%): ¹H NMR(CDCl₃) δ 4.68-4.61 (m, 1H), 3.91-3.79 (m, 4H), 1.99 (s, 3H), 0.80 (s,3H), 0.79 (s, 3H); ¹³C NMR (CDCl₃) δ 170.6, 119.3, 73.6, 65.1, 64.4,53.9, 50.2, 45.8, 44.5, 36.7, 35.6, 35.4, 34.1, 33.9, 31.2, 30.6, 28.3,27.4, 22.6, 21.4, 20.5, 14.3, 12.1.

(3α,5β,8α,9β,10α,13α,14β,16α)-16-Bromo-3-hydroxyandrostan-17-oneAcetate, Cyclic 17-(1,2-ethanediyl Acetal) (75)

To a solution of the compound 74 (1.22 g, 3.23 mmol) in THF (30 mL) wasadded pyridinium tribromide (1.55 g, 4.85 mmol) in THF (15 mL) at 0° C.After 1 h, the mixture was warmed to 23° C. After 1 h, aqueous Na₂S₂O₃(30 ml) was added and the product was extracted into EtOAc (3×100 mL).The combined extracts were dried and solvents removed to give an oil.The crude product was purified by flash column chromatography (silicagel, eluted with 15% EtOAc in hexanes) to give product 75 (1.41 g, 96%):¹H NMR (CDCl₃) δ 4.67-4.60 (m, 1H), 4.48-4.44 (m, 1H), 4.21-4.05 (m,2H), 3.93-3.84 (m, 2H), 1.98 (s, 3H), 0.83 (s, 3H), 0.78 (s, 3H); ¹³CNMR (CDCl₃) δ 170.5, 116.7, 73.4, 66.4, 66.0, 55.4, 53.7, 48.2, 45.4,44.5, 36.5, 35.4, 35.3, 35.1, 33.8, 30.8, 30.4, 28.1, 27.3, 21.4, 20.2,14.6, 12.1.

(3α,5β,8α,9β,10α,3α,14β)-3-Hydroxyandrost-15-en-17-one Cyclic17-(1,2-ethanediyl Acetal) (76)

To a solution of compound 75 (1.40 g, 3.08 mmol) in DMSO (30 mL) wasadded potassium t-butoxide (414 mg, 3.6 mmol) at 23° C. The mixture washeated to 85° C. for 16 h. After cooling, water (40 mL) was added andthe product extracted into EtOAc (3×100 mL). The combined extracts weredried and solvents removed to give product 76 as an oil. The crudeproduct was purified by flash column chromatography (silica gel, elutedwith 35% EtOAc in hexanes) to give product 76 (950 mg, 93%): ¹H NMR(CDCl₃) δ 6.14 (d, J=5.8 Hz, 1H), 5.67 (dd, J=5.6 Hz, 3.5 Hz, 1H),3.97-3.79 (m, 4H), 3.60-3.56 (m, 1H), 2.20-2.16 (m, 1H), 0.90 (s, 3H),0.83 (s, 3H); ¹³C NMR (CDCl₃) δ 136.5, 131.8, 119.5, 71.1, 65.2, 64.0,56.3, 54.9, 49.6, 44.9, 38.1, 36.7, 35.6, 32.8, 31.4, 31.3, 29.6, 28.4,20.3, 16.1, 12.3.

(3α,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrost-15-en-17-one (77)

To a solution of compound 76 (200 mg, 0.60 mmol) in acetone (20 mL) andwater (2 mL) was added PTSA (50 mg) at 23° C. After 2 h, NaHCO₃ (400 mg)was added. Solvent was removed and the residue was purified by flashcolumn chromatography (silica gel, eluted with 35% EtOAc in hexanes) togive product 77 (158 mg, 91%): ¹H NMR (CDCl₃) δ 7.49 (d, J=5.9 Hz, 1H),5.99 (dd, J=5.9 Hz, 3.1 Hz, 1H), 3.59-3.52 (m, 1H), 1.02 (s, 3H), 0.84(s, 3H); ¹³C NMR (CDCl₃) δ 213.4, 158.7, 131.5, 70.8, 56.8, 55.6, 51.0,45.0, 37.9, 36.6, 35.8, 32.2, 31.2, 30.7, 29.0, 28.1, 20.6, 20.1, 12.3.

(3α,5β,8α,9β,10α,13α,14β,15α)-3-Hydroxy-15-methxoyandrostan-17-one (78)

To a solution of compound 77 (70 mg, 0.24 mmol) in MeOH was added 4.0 MNaOH (5 mL) (precooled to 0° C.) and H₂O₂ (2.5 mL) at 0° C. After 2 h,the product was extracted into EtOAc (3×100 mL) and the combinedextracts were washed with brine (3×50 mL). The combined extracts weredried and solvents removed to give an oil. The oil was purified by flashcolumn chromatography (silica gel, eluted with 40% EtOAc in hexanes) togive product 78 (60 mg, 77%): ¹H NMR (CDCl₃) δ 4.11-3.90 (m, 1H),3.62-3.54 (m, 1H), 3.23 (s, 3H), 2.64 (d, J=19.2 Hz, 1H), 2.29 (dd,J=19.2 Hz, 6.3 Hz, 1H), 1.08 (s, 3H), 0.85 (s, 3H); ¹³C NMR (CDCl₃) δ220.2, 76.5, 71.1, 56.9, 55.5, 54.9, 47.1, 45.0, 42.4, 38.1, 36.9, 35.7,32.7, 31.5, 31.4, 30.3, 28.3, 20.5, 17.4, 12.3.

(3α,5β,8α,9β,10α,13α,14β,15α)-15-Methxoyandrostan-3-ol (79)

To compound 78 (60 mg, 0.19 mmol) in MeOH/CH₂Cl₂ (3:1, 20 mL) was addedzinc dust (1.3 g, 20 mmol) and dropwise TMSCl (2.54 mL, 20 mmol) at 0°C. After 2 h, NaHCO₃ (2.02 g, 24 mmol) was added. After stirring for 5min, the mixture was filtered and the filtrate was concentrated. Theresidue was purified by flash column chromatography (silica gel, elutedwith 30% EtOAc in hexanes) to give product 79 (36 mg, 63%): 3.69-3.66(m, 1H), 3.61-3.55 (m, 1H), 3.19 (s, 3H), 0.92 (s, 3H), 0.83 (s, 3H);¹³C NMR (CDCl₃) δ 81.7, 71.4, 59.2, 56.3, 55.2, 45.1, 40.6, 40.3, 40.1,38.3, 37.1, 35.7, 32.2, 31.5, 31.3, 29.8, 28.6, 21.3, 19.5, 12.4.

(5β,8α,9β,10α,13α,14β,15α)-15-Methxoyandrostan-3-one (80)

To a solution of compound 79 (36 mg, 0.12 mmol) in CH₂Cl₂ (10 mL) wasadded Dess-Martin periodinane (424 mg, 1.0 mmol). After 1 h, water (20mL) was added and the product extracted into CH₂Cl₂ (3×50 mL). Thecombined extracts were dried and solvents removed to give an oil. Theoil was purified by flash column chromatography (silica gel, eluted with25% EtOAc in hexanes) to give product 80 (29 mg, 80%): ¹H NMR (CDCl₃) δ3.70-3.67 (m, 1H), 3.19 (s, 3H), 1.03 (s, 3H), 0.94 (s, 3H); ¹³C NMR(CDCl₃) δ 212.3, 81.6, 59.0, 56.3, 54.5, 46.9, 44.8, 40.6, 40.3, 40.0,38.7, 38.2, 35.9, 32.1, 30.9, 29.8, 28.8, 21.4, 19.5, 11.5.

(3β,5β,8α,9β,10α,13α,14β,15α)-15-Methxoyandrostan-3-ol (81, MQ-117)

K-Selectride (1M in THF, 0.50 mL) was added dropwise under N₂ to acooled solution (−78° C.) of compound 80 (29 mg, 0.095 mmol) inanhydrous THF (10 mL). After 2 hr stirring at −78° C., water (2 mL) wasadded and the reaction was allowed to reach room temperature. Then,aqueous NaOH (2 mL, 3 M), and 30% H₂O₂ (2 mL) were added and thereaction was stirred for 30 min. The product was extracted into CH₂Cl₂(2×50 mL), the combined extracts were washed with aqueous HCl (1 N),saturated aqueous NaHCO₃, and brine and the solvent removed. Flashcolumn chromatography (silica gel, eluted with 10% EtOAc in hexanes)gave product 81 (MQ-117, 22 mg, 75%) as a white solid: mp 137-139° C.(EtOAc/hexanes); [α]_(D) ²³ +32 (c 0.10, CHCl₃). IR ν_(max) 3341, 2927,1451 cm⁻¹; ¹H NMR (CDCl₃) δ 4.04 (s, br, 1H), 3.70-3.68 (m, 1H), 3.19(s, 3H), 0.92 (s, 3H), 0.80 (s, 3H); ¹³C NMR (CDCl₃) δ 81.7, 66.6, 59.3,56.3, 55.1, 40.6, 40.3, 40.1, 39.3, 36.3, 35.9, 32.3, 32.2, 31.3, 29.8,29.0, 28.5, 20.8, 19.6, 11.2. Anal. (C₂₀H₃₄O₂) C, 78.38, H, 11.18. foundC, 78.50, H, 11.42.

In accordance with Scheme 8, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3β,5β,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)androstan-16-one (82)

To a cold (0° C.) stirred solution of compound 9 (145 mg, 0.5 mmol) inCH₂Cl₂ (5 mL) were added N,N-Diisopropyl ethyl amine (0.52, mL, 3 mmol)and chloromethyl methyl ether (0.15 mL, 2 mmol) and the reaction wasslowly brought to room temperature and allowed to stir at roomtemperature for another 16 h. Aqueous saturated NaHCO₃ was added and theproduct was extracted into CH₂Cl₂ (3×75 mL). The combined organicextracts were washed with brine, dried and concentrated to give an oilwhich was purified by flash column chromatography (silica gel, elutedwith 15-20% EtOAc in hexanes) to give product 82 as a white solid (159mg, 95%): mp 126-128° C.; IR ν_(max) 2934, 2845, 1742, 1438, 1385 cm⁻¹;¹H NMR δ 4.64 (s, 2H), 3.82 (s, 1H), 3.35 (s, 3H), 2.30 (m, 2H), 0.85(s, 3H), 0.81 (s, 3H); ¹³C NMR δ 218.8, 94.5, 71.4, 55.8, 55.1, 54.2,51.7, 39.6, 39.2, 39.1, 38.2, 36.0, 34.8, 33.54, 32.5, 32.2, 28.3, 26.2,20.3, 18.1, 11.3.

(3β,5β,8α,9β,10α,13α,14β,16α)-3-(Methoxymethoxy)androstan-16-ol (83)

To a cold (0° C.) solution of compound 82 (130 mg, 0.39 mmol) dissolvedin stirred EtOH (5 mL), was added NaBH₄ (38 mg, 1 mmol) and the mixturewas warmed to room temperature and stirred for 4 h. Water (70 mL) wasadded and the product was extracted into CH₂Cl₂ (3×50 mL). The combinedorganic extracts were washed with brine, dried and concentrated to givean oil. The oil was purified by flash column chromatography (silica gel,eluted with 10-25% EtOAc in hexanes) to give product 83 (110 mg, 85%):mp 82-84° C.; IR ν_(max) 3401, 2928, 1447, 1378 cm⁻¹; ¹H NMR δ 4.64 (s,2H), 4.34 (m, 1H), 3.82 (s, 1H), 3.35 (s, 3H), 2.16 (m, 1H), 0.93 (s,3H), 0.79 (s, 3H); ¹³C NMR δ 94.4, 71.9, 71.6, 55.1, 54.3, 54.0, 51.3,40.1, 39.7, 39.0, 37.1, 35.9, 35.2, 33.6, 32.7, 32.2, 28.5, 26.2, 20.4,19.1, 11.4.

(3β,5β,8α,9β,10α,13α,14β,16α)-16-Methoxy-3-(Methoxymethoxy)androstane(84)

A mixture of KH (50 wt % in paraffin, 160 mg, 2 mmol), compound 83 (80mg, 0.24 mmol)) and THF was refluxed for 2 hours under an N₂ atmosphere.The reaction was brought to room temperature and a large excess of MeI(5 mL) was added, and the mixture was heated at 50° C. for 16 h. Thereaction was cooled, the excess hydride was quenched carefully with2-propanol and water was added. The product was extracted into EtOAc andthe combined extracts were washed with brine, dried and concentrated togive an oil. The oil was purified by column chromatography (silica gel,eluted with 2-10% EtOAc in hexanes) to give product 84 (65 mg, 77%) as alow-melting white solid: mp 67-69° C.; IR ν_(max) 2920, 1447, 1378, 1221cm⁻¹; ¹H NMR δ 4.41 (s, 2H), 3.82 (b s, 2H), 3.35 (s, 3H), 3.23 (s, 3H),0.85 (s, 3H), 0.78 (s, 3H); ¹³C NMR δ 94.4, 81.1, 71.6, 56.6, 55.1,54.4, 53.3, 47.3, 39.8, 39.7, 39.1, 35.9, 35.2, 34.1, 33.6, 32.8, 32.2,28.5, 26.3, 20.5, 18.8, 11.3.

(3β,5β,8α,9β,10α,13α,14β,16α)-16-Methoxyandrostan-3-ol (85, KK-134)

To a methanolic solution (7 mL) of compound 84 (50 mg, 0.14 mmol) instirred MeOH (7 mL) was added a dry HCl solution (˜4 N) in MeOH (5 mL)and the mixture was stirred at room temperature for 17 h. The reactionwas made alkaline by adding aqueous saturated NaHCO₃ and the product wasextracted into CH₂Cl₂. The combined extracts were dried and concentratedto give crude product as an off-white solid which was purified by flashcolumn chromatography (silica gel, eluted with 20-35% EtOAc in hexanes)to give product 85 (KK-134) (35 mg, 81%) as a colorless solid: mp169-171° C.; [α]_(D)=+1.4 (c 0.14 CHCl₃); IR ν_(max) 3451, 2918, 1432,1378, 1246 cm⁻¹; ¹H NMR δ 4.04 (s, 1H), 3.83 (m, 1H), 3.24 (s, 3H), 1.68(m, 1H), 0.87 (s, 3H), 0.78 (s, 3H); ¹³C NMR δ 81.2, 66.5, 56.6, 54.4,53.3, 47.2, 39.8, 39.1 (2×C), 36.2, 35.8, 35.2, 34.1, 32.2, 32.1, 29.0,28.5, 20.5, 18.8, 11.2. Anal. (C₂₀H₃₄O₂): C, 78.38%; H, 11.18%. Found:C, 78.46%; H, 11.30%.

(3β,5β,8α,9β,10α,13α,14β)-16-Ethylidene-androstan-3-ol (86)

To a suspension of ethyltriphenylphosphonium bromide (1.85 g, 5 mmol) inTHF (15 mL) was added potassium t-butoxide in t-butyl alcohol (194 mgpotassium dissolved in 7.8 mL of t-butyl alcohol) and the resultingsolution was heated at reflux for 30 min. The solution became brightorange. Compound 85 (174 mg, 0.6 mmol) in THF (5 mL) was added and thereaction was refluxed for 2 h. The reaction was cooled, water was addedthe product was extracted into EtOAc (3×80 mL). The combined organicextracts were washed with brine, dried and solvent evaporated to give anoff-white solid. The crude product was purified by flash columnchromatography (silica gel, eluted with 25% EtOAc in hexanes) to yieldproduct 86 (160 mg, 88%) as a solid which was a mixture of the E/Z16-ethylidenes: IR ν_(max) 3293, 2926, 2849, 1448, 1377 cm⁻¹; ¹H NMR δ5.31 (b s, 1H), 4.05 (s, 1H), 0.80 (s, 3H), 0.73 & 0.71 (s, 3H); ¹³C NMRδ 141.9, 116.9, 116.2, 66.6, 54.5, 54.4, 5.7, 49.4, 45.1, 40.1, 39.1,38.7, 38.4, 36.2, 35.9, 35.3, 33.6, 32.2, 32.1, 29.8, 29.0, 28.5, 20.8,20.7, 18.2, 17.5, 14.6, 11.2.

(3β,5β,8α,9β,10α,13α,14β)-3-Benzyloxy-16-Ethylidene-androstane (87)

A stirred 60% suspension of sodium hydride (200 mg, 5 mmol) in mineraloil, compound 86 (151 mg, 0.5 mmol) and benzyl bromide (0.59 ml, 5 mmol)in THF (20 mL) was heated at reflux for 6 h. The reaction was cooled,aqueous saturated ammonium chloride was added and the product wasextracted into EtOAc (3×60 mL). The combined extracts were washed withbrine, dried and concentrated to give an oil. The oil was purified byflash column chromatography (silica gel, eluted with 2-5% EtOAc inhexanes). After purification, product 87 contained benzyl bromide whichwas removed by heating the isolated product at 160° C. under high vacuumto give product 87 (a mixture of the E/Z 16-ethylidenes, 157 mg, 80%) asa colorless oil: IR ν_(max) 2926, 2853, 1453, 1359 cm⁻¹; ¹H NMR δ7.30-7.18 (m, 5H), 5.23 (b s, 1H), 4.43 (apparent q, 2H, J=12.5 Hz),0.74 (s, 3H), 0.66 & 0.64 (s, 3H); ¹³C NMR δ 142.0, 139.5, 128.3, 127.4,127.2, 116.4, 116.1, 73.3, 69.6, 54.4, 53.7, 49.5, 45.1, 40.1, 39.6,38.8, 38.4, 36.1, 35.5, 35.4, 33.7, 33.1, 32.74, 32.74, 32.2, 29.9,29.7, 28.6, 25.7, 20.82, 20.76, 18.2, 17.5, 14.6, 11.5.

(3β,5β,8α,9β,10α,13α,14β,16α)-16-Acetyl-3-benzyloxyandrostane (88)

To an ice-cold solution of product 87 (130 mg, 0.33 mmol) in THF, wasadded a 1M solution of BH₃.THF complex (1 mL, 1 mmol) and the reactionwas stirred at 0° C. for 90 minutes. To this cold solution, were slowlyadded (in drops) 5 N aqueous NaOH (5 mL) and 30% H₂O₂ (5 mL) andstirring was continued at room temperature for 90 min. Water was addedand the product extracted into EtOAc (3×70 mL). The combined organicextracts were washed with brine, dried and solvent were removed to givea crude hydroboration alcohol product (not characterized) that wasdissolved in acetone (8 mL) and cooled to 0° C. Jones reagent was addeddrop wise until an orange color persisted. After 5 min, the excess Jonesreagent was consumed by adding few drops of 2-isopropanol. Water wasadded and the product extracted into EtOAc (3×60 mL). The combinedorganic extracts were washed with brine, dried and the solvent removedto give an oil. The oil was purified by flash column chromatography(silica gel, eluted 50% CH₂Cl₂ in hexanes) to give product 88 (90 mg,68%): mp: 135-138° C.; IR ν_(max) 2927, 2852, 1710, 1496, 1453, 1379,1359, 1208 cm⁻¹; ¹H NMR δ 7.30-7.15 (m, 5H), 4.43 (apparent q, 2H,J=11.1 Hz), 3.57 (s, 1H), 2.87 (m, 1H), 2.08 (s, 3H), 0.72 (s, 3H), 0.57(s, 3H); ¹³C NMR δ 210.7, 139.4, 128.3, 127.3 (2×C), 127.2 (2×C), 73.2,69.6, 54.9, 54.2, 49.4, 41.6, 40.8, 39.5, 38.9, 36.0, 35.3, 33.1, 32.8,32.2, 29.1, 28.8, 28.5, 25.6, 20.7, 18.3, 11.4.

(3β,5β,8α,9β,10α,13α,14β,16α)-16-Acetylandrostan-3-ol (89, KK-135)

Compound 88 (40 mg, 0.98 mmol) dissolved in EtOAc (15 mL) and Pd/C (100mg) was subjected to hydrogenolysis in a Parr Hydrogenator (H₂, 65 psi)for 3 days. The Pd/C was removed on a short silica gel column usingEtOAc as eluent and the solvent removed. The crude product was purifiedby flash column chromatography (silica gel, eluted with 30-40% EtOAc inhexanes) to give product 89 (KK-135, 25 mg, 81%) as a white solid: mp169-172° C.; [α]_(D) ²³=+18.6 (c 0.07, CHCl₃); IR ν_(max) 3486, 2928,1688, 1452, 1367, 1264, 1206 cm⁻¹; ¹H NMR δ 4.04 (d, 1H, J=2.8 Hz), 2.92(m, 1H), 2.15 (s, 3H), 0.77 (s, 3H), 0.64 (s, 3H); ¹³C NMR δ 210.6,66.5, 54.8, 54.3, 49.4, 41.6, 40.8, 39.1, 38.9, 36.2, 35.8, 35.2, 32.3,32.2, 29.1, 29.0, 28.8, 28.4, 20.7, 18.3, 11.2. Anal. (C₂₁H₃₄O₂): C,79.19%; H, 10.76%. Found: C, 79.09%; H,

In accordance with Scheme 9, the following compounds were prepared,using methods generally known in the art and as outlined below.

(3β,5α,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-androstan-16-one (90)

To a stirred cold (0° C.) solution of compound 25 (145 mg, 0.5 mmol) inCH₂Cl₂ (5 mL) were added N,N-diisopropyl ethyl amine (0.52, mL, 3 mmol)and chloromethyl methyl ether (0.15 mL, 2 mmol) and the reaction wasslowly brought to room temperature and allowed to stir for 16 h.Saturated aqueous NaHCO₃ was added and the product extracted into CH₂Cl₂(3×75 mL). The combined organic extracts were washed with brine, driedand concentrated to give an oil which was purified by flash columnchromatography (silica gel, eluted with 15-20% EtOAc in hexanes) to giveproduct 90 (150 mg, 90%) as a white solid: mp 108-110° C.; IR ν_(max)2581, 2930, 2884, 1735, 1449, 1410 cm⁻¹; ¹H NMR (CDCl₃) δ 4.66 (s, 2H),3.52 (m, 1H), 3.34 (s, 3H), 0.93 (s, 3H), 0.83 (s, 3H); ¹³C NMR (CDCl₃)δ 218.6, 94.5, 76.6, 55.8, 55.1, 51.6, 41.8, 40.4, 39.2, 39.1, 38.3,35.2, 35.0, 34.8, 33.4, 27.6, 26.9, 26.6, 23.2, 20.2, 18.0.

(3β,5α,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-androst-16-en-16-ol16-(1,1,1-trifluoromethanesulfonate) (91)

To a stirred cold (−78° C.) THF solution of compound 90 (130 mg, 0.39mmol) and N-phenyl bis(trifluoromethanesulfonimide) (357 mg, 1 mmol) wasadded potassium hexamethyldisilazide (0.5 M in toluene, 2 mL, 1 mmol)and the mixture was slowly warmed to room temperature and stirred for 15h. Water was added and the product extracted into EtOAc (3×70 mL). Thecombined extracts were washed with brine, dried and solvents removed togive a yellow oil. The crude product was purified by flash columnchromatography (silica gel, eluted with 2-3% EtOAc in hexanes) to giveproduct 91 (150 mg, 83%) as a colorless oil: IR ν_(max) 2934, 1634,1423, 1376, 1293, 1245, 1211, cm⁻¹; ¹H NMR (CDCl₃) δ 5.69 (d, 1H, J=1.6Hz), 4.68 (s, 2H), 3.53 (m, 1H), 3.37 (s, 3H), 2.30 (m, 2H), 0.94 (s,3H), 0.89 (s, 3H); ¹³C NMR (CDCl₃) δ 150.5, 129.3, 118.5 (q), 94.6,76.6, 75.3, 55.1, 54.6, 44.0, 41.9, 40.7, 35.5, 34.99, 34.96, 33.7,33.5, 32.2, 27.6, 26.9, 26.2, 23.2, 20.1, 16.9.

(3β,5α,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-androst-16-en-16-carbonitrile(92)

Compound 91 (116 mg, 0.25 mol) was dissolved in acetonitrile (15 mL),copper(I)iodide (15 mg) and sodium cyanide (50 mg) were added and thesolvent was refluxed under N₂. While refluxing,tertakis(triphenylphosphine)palladium (35 mg) was added and reflux wascontinued for 2 h. The reaction was cooled and aqueous NaHCO₃ solutionwas added. From the biphasic solution, the product was extracted intoEtOAc and the extracts were washed with brine, dried and the solventsremoved. The crude product was purified by flash column chromatography(silica gel, eluted with 5-15% EtOAc in hexanes) to give product 92 (60mg, 72%) as a white solid: mp 97-99° C.; IR ν_(max) 2931, 2864, 2218,1589, 1452, 1374, 1262, 1212 cm⁻¹; ¹H NMR (CDCl₃) δ 6.71 (d, 1H, J=1.6Hz), 4.68 (s, 2H), 3.53 (m, 1H), 3.36 (s, 3H), 2.38 (dd, 1H, J=14.9 Hz,6.3 Hz), 2.21 (m, 1H), 0.94 (s, 3H), 0.81 (s, 3H); ¹³C NMR (CDCl₃) δ160.2, 117.4, 113.3, 94.5, 76.6, 55.6, 55.1, 47.5, 41.9, 40.8, 36.2,34.9, 34.7, 34.5. 34.2, 33.5, 27.6, 26.9, 26.3, 23.2, 20.3, 15.8.

(3β,5α,8α,9β,10α,13α,14β)-3-Hydroxyandrost-16-ene-16-carbonitrile (93,KK-136)

To compound 92 (50 mg, 0.15 mmol) dissolved in MeOH (5 mL) was added adry HCl solution (˜4 N) in MeOH (4 ml) and the reaction was stirred atroom temperature for 2 h. The reaction was made basic by adding aqueoussaturated NaHCO₃ and the product was extracted into CH₂Cl₂. The CH₂Cl₂was dried and removed to give crude product 93 as an off-white solidwhich was purified by flash column chromatography (silica gel, elutedwith 40% EtOAc in hexanes) to give product 93 (40 mg, 93%) as a whitesolid: mp 195-197° C.; [α]_(D) ²³ +11.6 (c 0.06, CHCl₃); IR ν_(max)3391, 2928, 2860, 2219, 1589, 1453, 1373, 1263 cm⁻¹; ¹H NMR (CDCl₃) δ6.73 (d, 1H, J=1.6 Hz), 3.64 (m, 1H), 2.40 (m, 1H), 2.23 (m, 1H), 0.96(s, 3H), 0.83 (s, 3H); ¹³C NMR (CDCl₃) δ 160.2, 117.5, 113.3, 71.6,55.6, 47.6, 41.9, 40.8, 36.4, 35.2, 34.8, 34.3, 30.4, 26.9, 26.3, 23.2,20.3, 15.8. Anal. (C₂₀H₂₉NO): C, 80.21%; H, 9.76%; N, 4.68%. Found: C,79.88%; H, 9.96%; N, 4.67%.

(3β,5α,8α,9β,10α,13α,14β,16α)-3-Hydroxyandrost-16-carbonitrile (94,KK-137)

Compound 93 (85 mg) and 10% Pd—C (70 mg) in EtOAc (30 mL) washydrogenated in a Parr Hydrogenation apparatus at (H₂, 60 psi) for 15 h.The reaction was passed through a short silica gel column using 50%EtOAc in hexanes as eluent to give an off-white solid product.Recrystallization from diethyl ether gave product 94 (KK-137, 80 mg,94%) as a white solid: mp 155-157° C.; [α]_(D) ²³ +19 (c 0.1, CHCl₃); IRν_(max) 3400, 2930, 2862, 2234, 1450, 1382 cm⁻¹; ¹H NMR (CDCl₃) δ 3.61(m, 1H), 2.83 (m, 1H), 2.18 (m, 1H), 0.92 (s, 3H), 0.89 (s, 3H); ¹³C NMR(CDCl₃) δ 124.7, 71.5, 54.5, 45.1, 41.7, 41.6, 40.3, 38.3, 36.1, 35.6,35.3, 34.5, 32.2, 30.3, 26.8, 26.6, 23.2 (2×C), 20.3, 18.1. Anal.(C₂₀H₃₁NO): C, 79.68%; H, 10.36%; N, 4.65. Found: C, 79.42%; H, 10.54%;N, 4.60%.

In accordance with Scheme 10, the following compounds were prepared,using methods generally known in the art and as outlined below.

2-[(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrostan-16-ylidene]-acetonitrile(95, KK-138)

To a suspension of NaH (60% dispersion in mineral oil, 200 mg, 5 mmol)in dry THF (5 mL) at 0° C. under N₂, diethyl(cyanomethyl)phosphonate(0.83 mL, 5.13 mmol) was added dropwise. After disappearance of thesolid sodium hydride, compound 29 (145 mg, 0.5 mmol) in dry THF (10 mL)was added. The reaction was allowed to warm to room temperature andstirred for 15 h at room temperature. Aqueous NaHCO₃ was added and theproduct extracted into EtOAc. The EtOAc was washed with brine, dried andthe solvent removed. The residue was purified by flash columnchromatography (silica gel eluted with 20-35% EtOAc in hexanes) to giveproduct 95 as an inseparable mixture of E/Z nitriles (136 mg 87%): mp.162-172° C.; IR ν_(max) 3368, 2928, 2850, 2217, 1638, 1449, 1381, 1265cm⁻¹; ¹H NMR (CDCl₃) δ 5.26 (br s, 1H), 4.06 (br s, 1H), 2.80-2.04 (m,4H), 0.80 (s, 3H), 0.76 & 0.75 (s, 3H); ¹³C NMR (CDCl₃) δ 172.6, 172.4,117.3, 117.2, 92.6, 92.5, 66.4, 54.22, 54.17, 53.8, 53.5, 49.3, 41.3,40.9, 39.0, 38.0, 36.2, 35.81, 35.75, 35.2, 34.7, 34.08, 32.04, 29.0,28.9, 28.3, 20.5, 17.8, 17.6, 11.17, 11.15. Anal. (C₂₁H₃₁NO): C, 80.46%;H, 9.97%; N, 4.47%. Found: C, 80.81%; H, 10.28%; N, 4.52%.

(3β,5β,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-androst-16-en-16-ol16-(1,1,1-trifluoromethanesulfonate) (96)

Compound 96 (252 mg, 98%) was prepared as an oil from compound 9 usingthe procedure described for the preparation of compound 91. Compound 96had: ¹H NMR (CDCl₃) δ 5.67 (d, 1H, J=1.5 Hz), 4.64 (apparent q, 2H,J=6.6 Hz), 3.81 (m, 1H), 3.35 (s, 3H), 2.33 (m, 2H), 0.88 (s, 3H), 0.80(s, 3H); ¹³C NMR (CDCl₃) δ 150.6, 129.3, 118.5 (q), 94.5, 71.4, 55.0,54.5, 54.4, 43.9, 39.8, 36.1, 35.3, 33.5, 33.3, 32.4, 32.2, 31.6, 28.2,26.2, 20.2, 16.9, 11.2.

(3β,5β,8α,9β,10α,13α,14β)-3-(Methoxymethoxy)-androst-16-en-16-carbonitrile(97)

Compound 97 (140 mg, 98%) was prepared as an oil from compound 96 usingthe procedure described for the preparation of compound 92. Compound 97had: IR ν_(max) 2932, 2858, 2218, 1588, 1454, 1373, 1237, 1216 cm⁻¹; ¹HNMR (CDCl₃) δ 6.69 (d, 1H, J=1.5 Hz), 4.62 (2H, apparent q, J=7.1 Hz),3.81 (br s, 1H), 3.34 (s, 3H), 2.40-2.10 (m, 2H), 0.81 (s, 3H), 0.77 (s,3H); ¹³C NMR (CDCl₃) δ 160.1, 117.4, 113.2, 94.4, 71.3, 55.6, 55.0,54.4, 47.4, 39.7, 36.0, 34.5, 34.4, 33.7, 33.5, 32.5, 31.6, 28.2, 26.2,20.2, 15.8, 11.2.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxyandrost-16-ene-16-carbonitrile (98,KK-141)

Compound 98 (100 mg, 98%) was prepared as a white solid from compound 97using the procedure described for the preparation of compound 93.Compound 98 had: mp 247-249° C.; [α]_(D) ²³ +14.6 (c 0.07, CHCl₃); IRν_(max) 3484, 2934, 2915, 2857, 2220, 1588, 1452, 1371, 1355, 1247 cm⁻¹;¹H NMR (CDCl₃) δ 6.72 (d, 1H, J=2.0 Hz), 4.05 (br s, 1H), 2.42-2.18 (m,2H), 0.83 (s, 3H), 0.81 (s, 3H); ¹³C NMR (CDCl₃) δ 160.26, 117.48,113.28, 66.34, 55.59, 54.51, 47.48, 39.13, 36.28, 35.75, 34.53, 34.43,33.83, 31.90, 31.71, 28.91, 28.18, 20.31, 15.87, 11.10. Anal.(C₂₀H₂₉NO): C, 80.21%; H, 9.76%; N, 4.68%. Found: C, 80.39%; H, 9.75%;N, 4.69%.

(3β,5β,8α,9β,10α,13α,14β,16α)-3-Hydroxyandrost-16-carbonitrile (99,KK-142)

Compound 99 (41 mg, 92%) was prepared as a white solid from compound 98using the procedure described for the preparation of compound 94.Compound 99 had: mp: 206-208° C.; [α]_(D) ²³ +21 (c 0.05, CHCl₃); IRν_(max) 3478, 2929, 2850, 2234, 1450, 1383, 1265 cm⁻¹; ¹H NMR (CDCl₃) δ4.05 (br s, 1H), 2.83 (apparent q, J=8.0 Hz), 2.20 (m, 1H), 0.92 (s,3H), 0.79 (s, 3H); ¹³C NMR (CDCl₃) δ 124.86, 66.37, 54.61, 54.12, 45.16,41.57, 38.96, 38.24, 36.12, 35.73, 35.29, 32.18, 32.13, 28.94, 28.28,23.16, 20.37, 18.18, 11.14. Anal. (C₂₀H₃₁NO): C, 79.68%; H, 10.36%; N,4.65%. Found: C, 79.42%; H, 10.15%; N, 4.42%.

In accordance with Scheme 11, the following compounds were prepared,using methods generally known in the art and as outlined below.

(5β,8α,9β,10α,13α,14β,17α)-17-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-androstan-3-one(100)

Compound 29 (400 mg, 1.38 mmol), TBDMSCl (603 mg, 4 mmol), imidazole(340 mg, 5 mmol) and 4-DMAP (10 mg) was stirred in DMF (5 mL) at roomtemperature for 16 h. Aqueous saturated NaHCO₃ was added and the productextracted into ethyl acetate (3×50 mL). The combined extracts were driedand solvent removed give a crude white solid which was purified by flashcolumn chromatography (silica gel, eluted with 10% EtOAc in hexanes toyield product 100 as a white solid (500 mg, 90%): mp 131-133° C.; IRν_(max) 2934, 2856, 1716, 1461, 1471, 1446, 1251 cm⁻¹; ¹H NMR (CDCl₃) δ3.55 (t, 1H, J=8.0 Hz), 1.01 (s, 3H), 0.88 (s, 9H), 0.72 (s, 3H), 0.01(s, 3H), 0.00 (s, 3H); ¹³C NMR (CDCl₃) δ 212.1, 81.7, 54.1, 50.5, 46.8,44.7, 43.3, 38.6, 37.1, 35.7, 35.5, 31.3, 30.9, 28.8, 25.8, 23.5, 21.1,18.1, 11.5, 11.4, −4.5, −4.8. Anal. (C₂₅H₄₄O₂Si): C, 74.19%; H, 10.96%.Found: C, 74.04%; H, 11.12%.

(3β,5β,8α,9β,10α,13α,14β,17α)-17-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-methylandrostan-3-ol(101) and(3α,5β,8α,9β,10α,13α,14β,17α)-17-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-methylandrostan-3-ol(102)

To a cold solution (0° C.) of compound 100 (405 mg, 1 mmol) in 5 THF (5mL) was added MeMgCl (3M in diethyl ether, 2 mL) and the mixture wasstirred 0° C. for 2 h. Aqueous NH₄Cl was added and the product wasextracted into EtOAc (3×50 mL). The combined extracts were dried andsolvent removed to give products 101 and 102 as a mixture which waspurified and separated by flash column chromatography (silica gel,eluted with 15% EtOAc in hexanes) to yield less polar, first elutedproduct 102 (210 mg, 50%) and more polar, second eluted product 101 (190mg, 45%) as white solids.

Compound 101 had: m.p. 154-156° C.; IR ν_(max) 3267, 2928, 2856, 1471,1462, 1449, 1249 cm⁻¹; ¹H NMR (CDCl₃) δ 3.53 (t, 1H, J=7.7 Hz), 1.24 (s,3H), 0.87 (s, 9H), 0.81 (s, 3H), 0.69 (s, 3H), 0.00 (s, 6H); ¹³C NMR δ81.8, 71.5, 54.8, 50.7, 44.4, 43.35, 43.35, 37.2, 36.6, 36.4, 36.1,35.6, 31.7, 30.9, 28.6, 26.6, 25.8, 23.5, 20.9, 18.1, 11.9, 11.4, −4.5,−4.8. Anal. (C₂₆H₄₈O₂Si): C, 74.22%; H, 11.50%. Found: C, 73.98%; H,11.68%.

Compound 102 had: m.p 54-56° C.; IR ν_(max) 3383, 2954, 2856, 1472,1462, 1446, 1250 cm⁻¹; ¹H NMR (CDCl₃) δ 3.54 (t, 1H, J=8.5 Hz), 1.19 (s,3H), 0.87 (s, 9H), 0.75 (s, 3H), 0.69 (s, 3H), 0.01 (s, 3H), 0.00 (s,3H).; ¹³C NMR (CDCl₃) δ 81.8, 69.7, 54.5, 50.7, 43.3, 41.8, 41.2, 37.2,35.6, 34.9, 34.0, 31.6, 31.6, 30.9, 28.4, 25.8, 23.5, 20.6, 18.1, 11.4,11.2, −4.5, −4.8. Anal. (C₂₆H₄₈O₂Si): C, 74.22%; H, 10.50%. Found: C,74.24%; H, 11.50%.

(3β,5β,8α,9β,10α,13α,14β,17a)-3-Methylandrostane-3,17-diol (103)

Compound 101 (170 mg, 0.40 mmol) and 3 N HCl (2 mL) in THF (5 mL) wasstirred at room temperature for 6 h. Aqueous NaHCO3 was added and theproduct extracted into EtOAc. Solvent removal gave an oil, which waspurified by flash column chromatography (silica gel, eluted with 30%EtOAc in hexanes) to give product 103 as a white solid (100 mg, 81%): mp191-193° C.; IR ν_(max) 3232, 2922, 2856, 1445, 1445, 1378, 1337 cm⁻¹;¹H NMR (CDCl₃) δ 3.62 (t, 1H, J=8.5 Hz), 1.24 (s, 3H), 0.82 (s, 3H),0.73 (s, 3H); ¹³C NMR (CDCl₃) δ 81.9, 71.4, 54.6, 51.0, 44.3, 43.3,43.0, 36.7, 36.6, 36.4, 36.1, 35.5, 31.6, 30.5, 28.5, 26.6, 23.3, 20.8,11.9, 11.1. Anal. (C₂₀H₃₄O₂): C, 78.38%; H, 11.18%. Found: C, 78.18%; H,10.99%.

(3β,5β,8α,9β,10α,13α,14β)-3-Hydroxy-3-methylandrostan-17-one (104,KK-23)

Compound 102 (90 mg, 0.29 mmol), PCC (215.6 mg, 1 mmol) and sodiumacetate (82 mg) in CH₂Cl₂ was stirred at room temperature for 2 h. Thereaction was passed through a silica gel column and purified by elutionwith 20% EtOAc in hexanes to give product 104 as a white solid (80 mg,90%) which was re-crystallized from acetone-water: mp 183-185° C.;[α]_(D) ²³ −100.0 (c 0.43, CHCl₃); IR ν_(max) 3468, 2967, 2922, 2856,1732, 1451, 1377 cm⁻¹; ¹H NMR (CDCl₃) δ 1.18 (s, 3H), 0.79 (s, 3H), 0.77(s, 3H); ¹³C NMR δ (CDCl₃) 221.4, 71.3, 54.5, 51.4, 47.8, 44.2, 43.1,36.5, 36.3, 36.1, 35.8, 35.0, 31.5, 30.8, 28.3, 26.6, 21.7, 20.4, 13.8,11.8. Anal. (C₂₀H₃₂O₂): C, 78.90%; H, 10.59%. Found: C, 78.92%; H,10.42%.

In accordance with Scheme 12, the following compounds were prepared,using methods generally known in the art and as outlined below.

(5α,8α,9β,10α,13α,14β,17α)-17-Hydroxyandrostan-3-one (105)

This compound was prepared as previously described. (Hu, Y. F.; Wittmer,L. L.; Kalkbrenner, M.; Evers, A. S.; Zorumski, C. F.; Covey, D. F.Neurosteroid analogues. Part 5. Enantiomers of neuroactive steroids andbenz[e]indenes: total synthesis, electrophysiological effects onGABA_(A) receptor function and anesthetic actions in tadpoles. J. Chem.Soc. Perkin Trans. 1 1997, 3665-3671.)

(3β,5α,8α,9β,10α,13α,14β,17α)-3-Methylandrostane-3,17-diol (106) and(3α,5α,8α,9β,10α,13α,14β,17α)-3-Methylandrostane-3,17-diol (107)

To a cold solution (0° C.) of compound 105 (300 mg, 1.03 mmol) in THF (5mL) was added MeLi (1.6 M in diethylether, 4 mL, 6.4 mmol) and thereaction was stirred at 0° C. for 6 h. Saturated aqueous NH₄Cl was addedand the products extracted into EtOAc (3×50 mL). The combined extractswere dried and the solvent removed to give a solid. Products 106 and 107were purified and separated by flash column chromatography (silica gel,eluted with 20-30% EtOAc in hexanes) to yield to yield less polar, firsteluted product 107 (125 mg, 39%) and more polar, second eluted product106 (65 mg, 20%) as white solids. Unreacted compound 105 (85 mg, 28%)was also recovered.

Compound 106 had: mp 212-214° C.; IR ν_(max) 3306, 2894, 2861, 1442,1406, 1378, 1367, 1356 cm⁻¹; ¹H NMR (CDCl₃) δ 3.57 (s, 1H, J=8.5 Hz),1.19 (s, 3H), 0.89 (s, 3H), 0.65 (s, 3H); ¹³C NMR (CDCl₃) δ 81.9, 72.1,51.1, 43.1, 41.3, 41.2, 40.0, 36.9, 35.8, 35.3, 35.1, 34.8, 30.6, 26.9,26.4, 25.9, 23.5, 23.4, 20.4, 11.1.

Compound 107 had: mp 105-107° C.; IR ν_(max) 3337, 2922, 2858, 1446,1374, 1265 cm⁻¹; ¹H NMR (CDCl₃) δ 3.61 (t, J=8.0 Hz), 1.22 (s, 3H), 0.98(s, 3H), 0.72 (s, 3H); ¹³C NMR (CDCl₃) δ 81.9, 70.2, 51.0, 43.1, 39.9,39.5, 38.4, 36.9, 35.7, 34.6, 33.7, 32.0, 31.6, 30.5, 26.5, 25.9, 23.6,23.3, 20.6, 11.1.

(3β,5α,8α,9β,10α,13α,14β)-3-Hydroxy-3-methylandrostan-17-one (108,KK-26)

Compound 106 (55 mg, 0.18 mmol), PCC (150 mg, 0.7 mmol) and sodiumacetate (58 mg, 0.7 mmol)) in CH₂Cl₂ were stirred at room temperaturefor 2 h. The reaction was passed through a silica gel column andpurified by elution with 20% EtOAc in hexanes to give product 108 as awhite solid (49 mg, 89%). mp low melting, <50° C.; [α]_(D) ²³ −77.8 (c0.65, CHCl₃); IR ν_(max) 3440 2934, 2861, 1732, 1470, 1454, 1373, 1273cm⁻¹; ¹H NMR (CDCl₃) δ 3.60-3.30 (b s, 1H), 2.37 (dd, 1H, J=19.2, 8.8Hz), 1.19 (s, 3H), 0.90 (s, 3H) and 0.78 (s, 3H); ¹³C NMR (CDCl₃) δ221.2, 72.0, 51.5, 47.8, 41.3, 41.1, 40.1, 35.9, 35.3, 35.2, 35.2, 34.7,31.7, 26.7, 26.3, 25.2, 23.4 21.7, 20.1, 13.7. Anal. (C₂₀H₃₂O₂): C,78.90%; H, 10.59%. Found: C, 79.00%; H, 10.68%.

[³⁵S]-TBPS Displacement

The IC₅₀ values for the compounds of the examples as non-competitivedisplacers of [³⁵S]-TBPS from the picrotoxin binding site on GABA_(A)receptors are reported in Table 1.

TABLE 1 Inhibition of [³⁵S]-TBPS Binding Com- pound IC₅₀ n_(Hill) KK-18 627 ± 100 1.31 ± 0.22 KK-23 185 ± 28 0.94 ± 0.12 KK-26 290 ± 33 1.15 ±0.13 KK-97 112 ± 7  0.94 ± 0.05 KK-102 146 ± 18 0.98 ± 0.11 KK-103 238 ±21 0.86 ± 0.06 KK-114 1,520 ± 240  1.06 ± 0.14 KK-117 198 ± 25 0.98 ±0.11 KK-122  83 ± 11 1.15 ± 0.15 KK-134 92 ± 9 0.89 ± 0.07 KK-135 184 ±11 1.05 ± 0.06 KK-136 335 ± 27 1.01 ± 0.07 KK-137 22 ± 4 0.86 ± 0.09KK-138 32 ± 3 1.00 ± 0.08 KK-141 154 ± 19 1.10 ± 0.13 KK-142 29 ± 3 0.81± 0.05 MQ-35 81 ± 8 0.92 ± 0.07 MQ-117 19 ± 8 0.54 ± 0.08 MQ-124  8950 ±1860 1.02 ± 0.10 MQ-125 121 ± 10 0.95 ± 0.07

Results presented are from duplicate experiments performed intriplicate. Error limits are calculated as standard error of the mean.Methods used are known in the art (see, e.g., Jiang, et al.,Neurosteroid analogues. 9. Conformationally constrained pregnanes:structure-activity studies of 13,24-cyclo-18,21-dinorcholane analoguesof the GABA modulatory and anesthetic steroids (3α,5α)- and(3α,5β)-3-hydroxypregnan-20-one. J. Med. Chem. 2003, 46, 5334-5348).

Electrophysiology Results

The compounds of the present disclosure were evaluated for the abilityto potentiate chloride currents mediated by 2 μM GABA at rat α₁β₂γ_(2L)type GABA_(A) receptors expressed in Xenopus laevis oocytes and theresults are shown in Table 2.

TABLE 2 Modulation of Rat α₁β₂γ_(2L) GABA_(A) Receptor Function Oocyteelectrophysiology Com- (gating) pound 0.1 μM 1.0 μM 10 μM 10 μM KK-181.07 ± 0.05 1.64 ± 0.11  9.34 ± 1.36 0.13 ± 0.12 KK-23 1.11 ± 0.15 3.31± 0.43 19.74 ± 5.64 0.09 ± 0.02 KK-26 1.38 ± 0.10 5.10 ± 0.64 23.74 ±2.88 0.49 ± 0.18 KK-97 1.75 ± 0.24 6.15 ± 0.41 30.62 ± 2.14 0.16 ± 0.04KK-102 1.20 ± 0.02 4.23 ± 0.24 13.91 ± 1.38 0.04 ± 0.0  KK-103 0.97 ±0.02 2.43 ± 0.02 10.52 ± 0.61 0.02 ± 0.01 KK-114 0.93 ± 0.02 1.13 ± 0.02 3.56 ± 0.15 0.01 ± 0.02 KK-117 1.21 ± 0.02 3.67 ± 0.33 12.21 ± 1.260.05 ± 0.03 KK-122 1.41 ± 0.07 6.48 ± 0.40 16.00 ± 2.21 0.08 ± 0.03KK-134 1.16 ± 0.07 5.22 ± 1.09  8.27 ± 1.27 0.04 ± 0.05 KK-135 1.17 ±0.09 3.26 ± 0.31  6.21 ± 0.31 −0.04 ± 0.06  KK-136 0.98 ± 0.02 1.98 ±0.14 10.04 ± 1.26 0.29 ± 0.25 KK-137 2.32 ± 0.17 7.08 ± 0.54 10.17 ±0.68 −0.04 ± 0.08  KK-138 1.63 ± 0.23 5.87 ± 1.65 10.16 ± 3.18 0.14 ±0.06 KK-141 1.08 ± 0.11 1.35 ± 0.08  1.58 ± 0.13 0.08 ± 0.06 KK-142 2.20± 0.20 8.83 ± 3.12 13.32 ± 4.54 0.03 ± 0.01 MQ-35 1.42 ± 0.02 7.72 ±0.39 34.70 ± 1.69 0.15 ± 0.04 MQ-117 3.43 ± 0.29 11.10 ± 1.16  26.20 ±2.91 0.06 ± 0.02 MQ-124 0.68 ± 0.03 0.85 ± 0.03  1.57 ± 0.05 −0.01 ±0     MQ-125 1.19 ± 0.18 5.02 ± 0.40 14.08 ± 2.23 0.43 ± 0.41

The GABA concentration used for the control response was 2 μM. Eachcompound was evaluated on at least four different oocytes at theconcentrations indicated, and the results reported are the ratio ofcurrents measured in the presence/absence of added compound. Gatingrepresents direct current gated by 10 μM compound in the absence ofGABA, and this current is reported as the ratio of compound onlycurrent/2 M GABA current. Error limits are calculated as standard errorof the mean (N≥4). Receptor expression and whole-cell and single-channelrecordings were carried out as described previously (see Jiang, et al.,Neurosteroid analogues. 9. Conformationally constrained pregnanes:structure-activity studies of 13,24-cyclo-18,21-dinorcholane analoguesof the GABA modulatory and anesthetic steroids (3α,5α)- and(3α,5β)-3-hydroxypregnan-20-one. J. Med. Chem. 2003, 46, 5334-5348).

Tadpole Loss of Righting and Swimming

Table 3 discloses the anesthetic effects of the compounds of the presentdisclosure. In particular, the anesthetic effect of the compounds of thepresent disclosure on Loss of Righting Reflex (LRR) and Loss of SwimmingReflex (LSR).

TABLE 3 Tadpole Loss of Righting (LRR) & Loss of Swimming (LSR) EC₅₀Values (μM) Reflexes by Analogues Tadpole Tadpole Tadpole Tadpole Com-LRR LRR LSR LSR pound EC₅₀ (μM) n_(Hill) EC₅₀ (μM) n_(Hill) KK-18 3.20 ±2.03 −1.98 ± 2.03 >10 — KK-23 0.93 ± 0.53 −1.39 ± 0.86 2.81 ± 0.01 −21 ±0.5 KK-26 1.88 ± 0.0  −4.68 ± 0.01 5.48 ± 0.20 −33 ± 0.2 KK-97 0.49 ±0.11 −1.35 ± 0.31 1.73 ± 0.03 −36 ± 0.1 KK-102 1.21 ± 0.42 −4.29 ± 6.635.48 ± 0.12 −33 ± 0.1 KK-103 1.16 ± 0.21 −4.04 ± 4.06 5.48 ± 0.12 −33 ±0.1 KK-114 3.64 ± 2.17 −4.32 ± 11.8 >10 — KK-117 0.59 ± 0.07 −1.84 ±0.32 2.94 ± 0.0  −20 ± 0.6 KK-122 0.34 ± 0.4  −2.75 ± 1.13 1.73 ± 0.03−36 ± 0.1 KK-134 10/10^(a) — 10/10^(a) — KK-135 10/10^(a) — 10/10^(a) —KK-136 0.48 ± 0.02 −2.32 ± 0.12 1.73 ± 0.03 −36 ± 0.1 KK-137 0.13 ± 0.0 −2.13 ± 0.07 0.55 ± 0.01 −33 ± 0.1 KK-138 0.14 ± 0.0  −1.94 ± 0.08 0.87± 0.0  −20 ± 0.0 KK-141  5/10^(b) —  0/10^(c) — KK-142 10/10^(a) —10/10^(a) — MQ-35 0.55 ± 0.09 −2.90 ± 0.1  1.73 ± 0.04 −36 ± 0.1 MQ-1170.079 ± 0.003 −1.94 ± 0.12 0.33 ± 0.0  −19 ± 0.5 MQ-124 >10^(d) —  >10^(e) — MQ-125 10/10^(a) — 10/10^(a) — ^(a)All tadpoles lost LRR andLSR at a concentration of 3 μM. ^(b)5/10 tadpoles lost LRR at aconcentration of 3 μM. ^(c)0/10 tadpoles lost LSR at a concentration of3 μM. ^(d)0/10 tadpoles lost LRR at a concentration of 10 μM. ^(e)0/10tadpoles lost LSR at a concentration of 10 μM.

Methods used are known in the art (see, e.g., Jiang, et al.,Neurosteroid analogues. 9. Conformationally constrained pregnanes:structure-activity studies of 13,24-cyclo-18,21-dinorcholane analoguesof the GABA modulatory and anesthetic steroids (3α,5α)- and(3α,5β)-3-hydroxypregnan-20-one. J. Med. Chem. 2003, 46, 5334-5348).Error limits are calculated as standard error of the mean (N=10 or moreanimals at each of five or more different concentrations).

Mouse Behavioral Data

FIG. 1 is a graphical depiction of the duration of anesthesia (LRR)induced by tail vein injection of alphaxalone, compound 9 (MQ-35; ent-7)and compound 28 (KK-122, ent-9). The compounds were dissolved in 22.5%aqueous 2-(hydroxypropyl)-β-cyclodextrin. For compound 28, serialdilutions of a 8 mg/kg stock solution with 0.9% saline were made toobtain the lower doses tested.

The duration of anesthesia, defined as the loss of righting reflex isshown in FIG. 1. The potency, rate of onset, and rate of recovery forcompounds MQ-35 and KK-122 relative to these parameters for anestheticsteroid alphaxalone were made using tail vein injections in mice. As canbe seen from the results in FIG. 1, a 16 mg/kg dose of alphaxalonecaused LRR of about 4 minutes. At a dose of 8 mg/kg, compound MQ-35caused LRR of about 3 minutes and at a dose of 16 mg/kg duration of LRRwas increased to about 7 minutes.

For compound KK-122, no LRR was observed at a dose of 1 mg/kg and LRR ofabout 1 minute was observed at a threshold dose of 2 mg/kg. At 4 mg/kg,LRR induced by KK-122 lasted about 5 minutes and at a dose of 8 mg/kgLRR lasted for about 9 minutes. For all three compounds, the onset ofanesthesia was immediate (i.e., less than 30 seconds) and recovery wascharacterized by a rapid progression over 1-2 minutes from an initialreturn of leg movement followed by righting and subsequent walkingaround the cage.

General Methods

The compounds discussed in the present disclosure were produced asdiscussed elsewhere throughout this disclosure and by the followingmethods. Solvents were either used as purchased or dried and purified bystandard methodology. Extraction solvents were dried with anhydrousNa₂SO₄ and after filtration, removed on a rotary evaporator. Flashchromatography was performed using silica gel (32-63 μm) purchased fromScientific Adsorbents (Atlanta, Ga.). Melting points were determined ona Kofler micro hot stage and are uncorrected. FT-IR spectra wererecorded as films on a NaCl plate. NMR spectra were recorded in CDCl₃ atambient temperature at 300 MHz (¹H) or 74 MHz (¹³C). Purity wasdetermined by TLC on 250 μm thick UNIPLATES™ from Analtech (Newark,Del.). All pure compounds (purity >95%) gave a single spot on TLC.Elemental analyses were performed by M-H-W Laboratories (Phoenix,Ariz.).

EQUIVALENTS AND SCOPE

In view of the above, it will be seen that the several advantages of thedisclosure are achieved and other advantageous results attained. Asvarious changes could be made in the above processes and compositeswithout departing from the scope of the disclosure, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

When introducing elements of the present disclosure or the variousversions, embodiment(s) or aspects thereof, the articles “a”, “an”,“the” and “said” are intended to mean that there are one or more of theelements. It is also noted that the terms “comprising”, “including”,“having” or “containing” are intended to be open and permits theinclusion of additional elements or steps.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R₁ is H; R₂ isH, optionally substituted C₁-C₄ alkoxy, aryloxy, morpholinyl, optionallysubstituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, or—O—C(O)—R_(x), where R_(x) is optionally substituted C₁-C₂₀ alkyl; R₃ isH, OH, optionally substituted C₁-C₄ alkoxy, optionally substituted C₂-C₄alkenoxy, optionally substituted C₂-C₄ alkynoxy, aryloxy, acetyl,substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R_(u), whereR_(u) is optionally substituted C₁-C₂₀ alkyl; R₄ is H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(t), where R_(t) is optionallysubstituted C₁-C₂₀ alkyl; with the proviso that when R₃ and R₄ are takentogether, R₃ and R₄ combine to form ═O or ═CR_(y), (where R_(y) is CN,CH₂NH₂, C(O)—O—R_(w) (where R_(w) is H, optionally substituted C₁-C₁₀ oroptionally substituted phenyl), or CH₂OR_(v) (where R_(v) is H,optionally substituted C₁-C₁₀, optionally substituted phenyl, oroptionally substituted napthyl)); R₅ is H; R₆ is H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(r), where R_(r) is optionallysubstituted C₁-C₂₀ alkyl; R₇ is H, optionally substituted C₁-C₄ alkoxy,optionally substituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substitutedCOCH₃; R₈ is H, optionally substituted C₁-C₄ alkoxy, optionallysubstituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy,spirooxirane, cyano, ═O, ═CHCN, nitro or optionally substituted COCH₃;R₉ is H, optionally substituted C₁-C₄ alkoxy, spiroepoxide or ═O; R₁₀ isH or optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; R₁₁ is H or optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl; R₁₂ is H or optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl; - - - denotes an optional, additional C—Cbond, resulting in a C═C bond between C₄-C₅, C₅-C₆, C₆-C₇, C₇-C₈,C₁₅-C₁₆, and/or C₁₆-C₁₇; and, with the provisos that: at least one ofR₇, R₈ and R₉ is not hydrogen; when R₁-R₈ and R₁₂ are H, R₁₀ and R₁₁ areCH₃, R₉ is other than ═O or spiroepoxide; when R₁-R₈ and R₁₁-R₁₂ are H,R₁₀ is CH₃, and the C₅—H is in the alpha position, R₉ is other than ═O.2. The compound of claim 1, wherein R₂, when not H and no double bond ispresent between C₄-C₅, is in the alpha configuration.
 3. The compound ofclaim 1, wherein R₈, when not ═O, is in the alpha configuration.
 4. Thecompound of claim 1, wherein R₉, when not ═O, is in the alphaconfiguration.
 5. The compound of claim 1, wherein R₂ is selected fromthe group consisting of H and methoxy.
 6. The compound of claim 1,wherein R₃ is H.
 7. The compound of claim 1, wherein R₄ is H.
 8. Thecompound of claim 1, wherein R₆ is H.
 9. The compound of claim 1,wherein R₇ is selected from the group consisting of H and —OCH₃.
 10. Thecompound of claim 1, wherein R₈ is selected from the group consisting of═O, —OCH₃, COCH₃, CN and ═CHCN.
 11. The compound of claim 1, wherein R₉is ═O.
 12. The compound of claim 1, wherein R₁₀ is selected from thegroup consisting of H and methyl.
 13. The compound of claim 1, whereinR₁₁ is selected from the group consisting of H and methyl.
 14. Thecompound of claim 1, wherein R₁₂ is selected from the group consistingof H and methyl.
 15. The compound of claim 1 selected from the groupconsisting of:

and pharmaceutically acceptable salts thereof.
 16. A method of inducinganesthesia in a subject in need thereof, said method comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R₁ is H; R₂ isH, optionally substituted C₁-C₄ alkoxy, aryloxy, morpholinyl, optionallysubstituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy, or—O—C(O)—R_(x), where R_(x) is optionally substituted C₁-C₂₀ alkyl; R₃ isH, OH, optionally substituted C₁-C₄ alkoxy, optionally substituted C₂-C₄alkenoxy, optionally substituted C₂-C₄ alkynoxy, aryloxy, acetyl,substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R_(u), whereR_(u) is optionally substituted C₁-C₂₀ alkyl; R₄ is H, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(t), where R_(t) is optionallysubstituted C₁-C₂₀ alkyl; with the proviso that when R₃ and R₄ are takentogether, R₃ and R₄ combine to form ═O or ═CR_(y), (where R_(y) is CN,CH₂NH₂, C(O)—O—R_(w) (where R_(w) is H, optionally substituted C₁-C₁₀ oroptionally substituted phenyl), or CH₂OR_(v) (where R_(v) is H,optionally substituted C₁-C₁₀, optionally substituted phenyl, oroptionally substituted napthyl)); R₅ is H; R₆ is H, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl or —O—C(O)—R_(r), where R_(r) is optionallysubstituted C₁-C₂₀ alkyl; R₇ is H, optionally substituted C₁-C₄ alkoxy,optionally substituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substitutedCOCH₃; R₈ is H, optionally substituted C₁-C₄ alkoxy, optionallysubstituted C₂-C₄ alkenoxy, optionally substituted C₂-C₄ alkynoxy,spirooxirane, cyano, ═O, ═CHCN, nitro or optionally substituted COCH₃;R₉ is H, optionally substituted C₁-C₄ alkoxy, spiroepoxide or ═O; R₁₀ isH or optionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, or optionally substituted C₂-C₄ alkynyl; R₁₁ is H or optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, oroptionally substituted C₂-C₄ alkynyl; R₁₂ is H or optionally substitutedC₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, or optionallysubstituted C₂-C₄ alkynyl; - - - denotes an optional, additional C—Cbond, resulting in a C═C bond between C₄-C₅, C₅-C₆, C₆-C₇, C₁₅-C₁₆,and/or C₁₆-C₁₇; and, with the provisos that: at least one of R₇, R₈ andR₉ is not hydrogen; when R₁-R₈ and R₁₂ are H, R₁₀ and R₁₁ are CH₃, R₉ isother than ═O or spiroepoxide; when R₁-R₈ and R₁₁-R₁₂ are H, R₁₀ is CH₃,and the C₅—H is in the alpha position, R₉ is other than ═O.